Aromatic amino-alcohol derivatives having anti-diabetic and anti-obesity properties, their preparation and their therapeutic uses

ABSTRACT

Compounds of formula (I): ##STR1## (wherein: R 0  is hydrogen, methyl or hydroxymethyl; R 1  is substituted alkyl; R 2  and R 3  are each hydrogen, halogen, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkyl, nitro, haloalkyl, or substituted alkyl; X is oxygen or sulfur; and Ar optionally substituted phenyl or naphthyl); and pharmaceutically acceptable salts thereof have a variety of valuable pharmaceutical activities, including anti-diabetic and anti-obesity activities; in addition, they are capable of treating or preventing hyperlipemia and hyperglycemia and, by inhibiting the action of aldose reductase, they can also be effective in the treatment and prevention of complications of diabetes.

This application is a Continuation, of application Ser. No. 08/178,465,filed Jan. 6, 1994 now abandoned, which is a Continuation of Ser. No.07/979,180 filed Nov. 20, 1992 (abandoned).

BACKGROUND TO THE INVENTION

The present invention relates to a series of compounds which arecharacterised by a 2-[2-(substituted phenyl-oxy, thio ormethyl)-1-methylethyl]aminoethanol structure and which have valuableanti-diabetic and anti-obesity activities; in addition, they are capableof treating or preventing hyperlipemia and hyperglycemia and, byinhibiting the action of aldose reductase, they can also be effective inthe treatment and prevention of complications of diabetes. They are alsoeffective in the treatment and prophylaxis of obesity-relatedhypertension and osteoporosis. The invention also provides processes forpreparing the compounds of the present invention, as well as methods andcompositions using them.

A number of compounds of this general type is known, and some have beendisclosed to have anti-diabetic and/or anti-obesity activity. The knowncompounds which are structurally related to the compounds of the presentinvention may be represented by the general formula (A): ##STR2##

For example, D. T. Collin et al. [J. Med. Chem., 13, 674-680 (1970)]disclose compounds in which Q represents, inter alia, an isopropylgroup, a t-butyl group or a 2-phenyl-1-methylethyl group, and at leastone of R^(A1), R^(A2) and R^(A3) represents a hydrogen atom, and theother two of R^(A1), R^(A2) and R^(A3) represent, for example, hydroxygroups, alkoxy groups, carboxy groups (or esterified carboxy groups) orhydroxymethyl groups. These compounds are said to have an agonisticactivity against the β-adrenergic receptors, and are not disclosed ashaving the same kinds of activities as do the compounds of the presentinvention.

UK Patent Specification No. 1 551 260 also discloses that compoundsrepresented by the general formula (A), but in which Q represents aphenylaminoethyl group, have the same activity.

UK Patent Specification No. 1 200 886 also discloses compoundsrepresented by the general formula (A), but in which Q represents ahydroxybenzyl, alkoxybenzyl or 2-phenoxy-1-methylethyl group, and thesecompounds are also alleged to have a β-adrenergic stimulant and blockingactivity.

European Patent Publication No. 6735 also discloses a series ofcompounds of formula (A) in which Q represents a group of formula (B):##STR3## wherein R^(A4) represents a carboxy group or a salt thereof, analkoxycarbonyl group having from 2 to 5 carbon atoms or analkylcarbamoyl group having from 2 to 5 carbon atoms; R^(A5) representsa hydrogen, chlorine or fluorine atom, a methyl group, a methoxy group,a hydroxy group, a carboxy group or a salt thereof, an alkyloxycarbonylgroup having from 2 to 5 carbon atoms or an alkylcarbamoyl group havingfrom 2 to 5 carbon atoms; R^(A6) represents a hydrogen atom, or amethyl, ethyl or propyl group; R^(A7) represents a hydrogen atom, or amethyl, ethyl or propyl group; X^(A) represents an oxygen atom or asingle bond; and Y^(A) represents an alkylene group having from 1 to 6carbon atoms or a single bond, and these are said to haveanti-hyperglycemia and anti-obesity activities.

European Patent Publication No. 21 636, which is currently thought torepresent the closest prior art to the present invention, disclosescompounds having the general formula (A) in which Q represents a groupof formula (B), and in which: R^(A1) and R^(A2) each represents ahydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group ora trifluoromethyl group, and R^(A1) and R^(A2) may be the same ordifferent; R^(A3) represents a hydrogen atom; R^(A4) represents ahydroxy group or a lower alkyl group substituted with a lower alkoxy orlower acyloxy group; R^(A5) represents a hydrogen atom; R^(A6) andR^(A7) each represents a hydrogen atom or a methyl group, and R^(A6) andR^(A7) may be the same or different; X^(A) represents an oxygen atom ora single bond; and Y^(A) represents a methylene or ethylene group. Theseare also said to have anti-hyperglycemia and anti-obesity activity.Certain of the compounds of the present invention are a selection fromthose disclosed in this document and have the advantages that they havelittle effect on the receptors of the central nervous system, such asthe muscarine, N-methyl-D-aspartate and serotonin (5-HT₁, 5-HT₂ and5-HT₃) receptors. They also have no effect on the cardiovascular systembecause they have no inotropic activity (right atrium) or chronotropicactivity (right atrium). As a result, the compounds of the presentinvention have far fewer side effects and can thus be expected to find awider range of practical uses.

European Patent Publication No. 25 331 discolses compounds having thegeneral formula (A), in which Q represents a group of formula (C):##STR4## and R^(A1), R^(A2) and R^(A3) are the same or different andeach represents a hydrogen, fluorine, chlorine or bromine atom or atrifluoromethyl group; R^(B1), R^(B2), R^(B3) and R^(B4) each representsa hydrogen atom or a lower alkyl group, and R^(B1), R^(B2), R^(B3) andR^(B4) may be the same or different; R^(B5) represents a carboxy group,a lower alkyl ester thereof or a group of formula --CONHR^(B6) (in whichR^(B6) represents a hydrogen atom or a lower alkyl group); and Y^(B)represents an alkylene group having 1 or 2 carbon atoms. These are saidto have anti-hyperglycemia and anti-obesity activity.

U.S. Pat. No. 4,338,333 discloses that compounds having the generalformula (A) in which Q represents a group of formula (B) and R^(A1)represents a hydrogen or halogen atom, or a hydroxy, hydroxymethyl ortrifluoromethyl group; R^(A2) and R³ are the same or different and eachrepresents a hydrogen or halogen atom or a hydroxy group; R^(A6) andR^(A7) are the same or different and each represents a hydrogen atom ora methyl group; R^(A4) represents a hydrogen atom; X^(A) represents anoxygen atom or a single bond; Y^(A) represents a methylene or ethylenegroup; and R^(A5) represents a group --O--Z^(A) --COOH, where Z^(A)represents an alkylene group having less than 3 carbon atoms or analkenylene group having less than 3 carbon atoms, and salts, esters andamides thereof have a preventative activity against hyperglycemia andobesity.

European Patent Publication No. 262 785, moreover, discloses that, ofthe compounds having this formula,2-[2-(4-carboxymethoxyphenyl)-1(R)-1-methylethyl]amino-1(R)-(3-chlorophenyl)ethanol and its methyl ester and pharmaceuticallyacceptable salts thereof (referred to as the "RR-isomer"), which mayoptionally contain some proportion of2-[2-(4-carboxymethoxyphenyl)-1(S)-1-methylethyl]amino-1(S)-(3-chlorophenyl)ethanoland its methyl ester and pharmaceutically acceptable salts thereof (the"SS-isomer"), provided that the content of the SS-isomer is not morethan 50% by weight of the mixture of RR- and SS-isomers, is particularlyeffective as an anti-hyperglycemic or anti-obese medicine.

We have now discovered a limited series of novel 2-[2-(substitutedphenyl-oxy, thio or methyl)-1-methylethyl]aminoethanol derivatives whichhave valuable anti-diabetic and anti-obesity activities, with a lowtoxicity, accompanied by much fewer side effects; the compounds of thepresent invention, moreover, have the ability to inhibit the action ofaldose reductase, and so they can also be effective in the treatment andprevention of complications of diabetes. They are also effective in thetreatment and prophylaxis of obesity-related hypertension andosteoporosis.

BRIEF SUMMARY OF INVENTION

It is, therefore, an object of the present invention to provide a seriesof compounds of this type.

It is a further, and more specific, object of the invention to providesuch compounds having anti-diabetic and anti-obesity activities, andpreferably having a low toxicity, accompanied by much fewer sideeffects.

It is a further object of the invention to provide methods andcompositions using these compounds.

Other objects and advantages will become apparent as the descriptionproceeds.

The compounds of the present invention are those compounds of formula(I): ##STR5## wherein: R⁰ represents a hydrogen atom, a methyl group ora hydroxymethyl group;

R¹ represents a substituted alkyl group having from 1 to 12 carbonatoms, which group is substituted by at least one substituent selectedfrom the group consisting of substituents A, defined below;

R² and R³ are independently selected from the group consisting of:hydrogen atoms; halogen atoms; hydroxy groups; alkoxy groups having from1 to 5 carbon atoms; carboxy groups; alkoxycarbonyl groups having from 2to 7 carbon atoms; alkyl groups having from 1 to 5 carbon atoms; nitrogroups; haloalkyl groups having from 1 to 4 carbon atoms; andsubstituted alkyl groups which have from 1 to 12 carbon atoms and whichare substituted by at least one substituent selected from the groupconsisting of substituents A, defined below;

X represents an oxygen or sulfur atom; and

Ar represents a group of formula (II) or (III): ##STR6## wherein: R⁴represents a hydrogen atom, a halogen atom, a hydroxy group, ahydroxymethyl group, an alkoxy group having from 1 to 5 carbon atoms, analkyl group having from 1 to 5 carbon atoms, an aliphatic carboxylicacyloxy group having from 1 to 6 carbon atoms, a nitro group, a cyanogroup, an aralkyloxy group, in which the aralkyl part is as definedbelow, an aryloxy group in which the aryl part is as defined below, anaryl group as defined below or a haloalkyl group having from 1 to 4carbon atoms;

R⁵ represents a hydrogen atom, a halogen atom, a hydroxy group, analkoxy group having from 1 to 5 carbon atoms, an alkyl group having from1 to 5 carbon atoms or a nitro group; and

R⁶ represents a hydrogen atom, a halogen atom, a hydroxy group, analkoxy group having from 1 to 5 carbon atoms or an alkyl group havingfrom 1 to 5 carbon atoms;

said aralkyl part is an alkyl group which has from 1 to 3 carbon atomsand which is substituted by 1 or 2 aryl groups as defined below;

said aryl groups are carbocyclic aryl groups which have from 6 to 10ring carbon atoms and which are unsubstituted or are substituted by atleast one substituent selected from the group consisting of substituentsB, defined below;

said substituents A are selected from the group consisting of carboxygroups, alkoxycarbonyl groups having from 2 to 7 carbon atoms,aryloxycarbonyl groups in which the aryl part is as defined above,aralkyloxycarbonyl groups in which the aralkyl part is as defined above,alkylcarbamoyl groups in which the alkyl part has from 1 to 6 carbonatoms, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups,carboxylic acyloxy groups having from 1 to 6 carbon atoms and2,4-dioxothiazolidin-5-yl groups; and

said substituents B are selected from the group consisting of halogenatoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groupshaving from 1 to 3 carbon atoms, nitro groups, haloalkyl groups havingfrom 1 to 4 carbon atoms and hydroxy groups;

and pharmaceutically acceptable salts thereof.

The invention also provides a pharmaceutical composition for thetreatment or prophylaxis of diabetes, obesity, hyperlipemia,hyperglycemia, complications of diabetes, obesity-related hypertensionand osteoporosis, which composition comprises an effective amount of anactive compound in admixture with a pharmaceutically acceptable carrieror diluent, wherein the active compound is selected from the groupconsisting of compounds of formula (I) and pharmaceutically acceptablesalts thereof.

The invention also provides a method for the treatment or prophylaxis ofdiabetes, obesity, hyperlipemia, hyperglycemia, complications ofdiabetes, obesity-related hypertension and osteoporosis in a mammal,which may be human, which method comprises administering to said mammalan effective amount of an active compound, wherein the active compoundis selected from the group consisting of compounds of formula (I) andpharmaceutically acceptable salts thereof.

The invention also provides processes for preparing the compounds of thepresent invention, which are described in more detail hereafter.

DETAILED DESCRIPTION OF INVENTION

In the compounds of the present invention, R¹ represents a substitutedalkyl group having from 1 to 12 carbon atoms, which group is substitutedby at least one substituent selected from the group consisting ofsubstituents A, defined above and exemplified below. This may be astraight or branched chain alkyl group having from 1 to 12 carbon atoms,and examples include the methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, isopropyl, isobutyl,sec-butyl, t-butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 3-hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-methylhexyl, 1-ethylpentyl and 1-propylbutyl groups. Of these, weprefer the straight or branched chain alkyl groups having from 1 to 6carbon atoms, and most prefer the straight or branched chain alkylgroups having from 1 to 3 carbon atoms.

This alkyl group represented by R¹ is substituted by at least one ofsubstituents A. There is no particular limitation on the number of suchsubstituents, except such as may be imposed by the number ofsubstitutable carbon atoms, or possibly by steric constraints. However,in general, we prefer that the number of substituents should be from 1to n where n is the number of hydrogen atoms in the unsubstituted alkylgroup or 8, whichever is the lesser. Thus, in the case of the methylgroup, the number of substituents is from 1 to 3; in the case of theethyl group, it is from 1 to 5; in the case of the propyl and isopropylgroups, it is from 1 to 7; and, in the case of the butyl and higheralkyl groups, it is from 1 to 8. In all cases, the maxima proposed maybe affected by steric effects, as is well known in the art. Examples ofsuch substituents A are as follows:

Substituent A may be a carboxy, carbamoyl, hydroxycarbamoyl, hydroxy or2,4-dioxothiazolidin-5-yl group.

Alterantively, where substituent A is an alkoxycarbonyl group, this maybe a straight or branched chain alkoxycarbonyl group having from 2 to 7carbon atoms, examples of which include the methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl and 2,2-dimethylpropoxycarbonyl groups, of which weprefer the straight or branched chain alkoxycarbonyl groups having from2 to 5 carbon atoms and most prefer the straight chain alkoxycarbonylgroups having 2 or 3 carbon atoms.

Where substituent A is an optionally substituted aryloxycarbonyl group,the aryl part is as defined above and exemplified below. These groupshave, in total, from 7 to 11 carbon atoms, and may be unsubstituted ormay be substituted by at least one of substitutents B, defined above andexemplified below. There are no particular limitations on the number ofsubstituents which may be used, except such as may be imposed by thenumber of substitutable positions and possibly by steric constraints;however, in general, from 1 to 5 substituents are preferred, from 1 to 3substituents being more preferred. Examples of unsubstitutedaryloxycarbonyl groups include the phenoxycarbonyl,1-naphthyloxycarbonyl and 2-naphthyloxycarbonyl groups. Examples ofsubstituted aryloxycarbonyl groups include any of the unsubstitutedgroups exemplified above but which is substituted by at least one ofsubstituents B, and specific examples of such substituted groups includethe o-, m- or p-fluorophenoxycarbonyl, o-, m- orp-chlorophenoxycarbonyl, o-, m- or p-methylphenoxycarbonyl, o-, m- orp-methoxyphenoxycarbonyl, o-, m- or p-nitrophenoxycarbonyl, o-, m- orp-trifluoromethylphenoxycarbonyl, and o-, m- or p-hydroxyphenoxycarbonylgroups. Of these, we prefer those aryloxycarbonyl groups which areunsubstituted or which have from 1 to 3 substituents selected from thegroup consisting of halogen atoms, alkyl groups having 1 or 2 carbonatoms, alkoxy groups having 1 or 2 carbon atoms and trifluoromethylgroups. Most preferred is the phenoxycarbonyl group which isunsubstituted or which has 1 or 2 substituents selected from the groupconsisting of fluorine atoms, chlorine atoms, methyl groups, methoxygroups and trifluoromethyl groups.

Where substituent A is an optionally substituted aralkyloxycarbonylgroup, the aralkyl part is as defined above. The unsubstituted group hasin total from 8 to 14 carbon atoms. Where the group is substituted,there is no particular limitation on the number of substituents, andthis is normally only constrained by the number of substitutablepositions and possibly by steric constraints. In general, from 1 to 5substituents are preferred, from 1 to 3 being more preferred. Where thegroup is substituted, the substitutent is at least one of substituentsB, defined above and exemplified below. The aralkyl part of the grouphas an alkyl part which is substituted by 1 or 2 aryl groups. Suitablealkyl groups having from 1 to 3 carbon atoms are the methyl, ethyl,propyl and isopropyl groups, and these may be substituted by 1 or 2 arylgroups, such as phenyl or naphthyl groups. Examples of unsubstitutedaralkyloxycarbonyl groups include the benzyloxycarbonyl,phenethyloxycarbonyl, 1-phenylethyloxycarbonyl,3-phenylpropyloxycarbonyl and naphthylmethoxycarbonyl groups. Examplesof substituted aralkyloxycarbonyl groups include any of theunsubstituted groups exemplified above but which is substituted by atleast one of substituents B, and specific examples of such substitutedgroups include the o-, m- or p-fluorobenzyloxycarbonyl, o-, m- orp-chlorobenzyloxycarbonyl, o-, m- or p-methylbenzyloxycarbonyl, o-, m-or p-methoxybenzyloxycarbonyl, o-, m- or p-nitrogenzyloxycarbonyl, o-,m- or p-trifluoromethylbenzyloxycarbonyl, o-, m- orp-hydroxybenzyloxycarbonyl, 3,5-di-t-butyl-4-hydroxybenzyloxycarbonyland 3,4,5-trimethoxybenzyloxycarbonyl groups. Of these, we prefer thosearalkyloxycarbonyl groups which are unsubstituted or which have from 1to 3 substituents selected from the group consisting of halogen atoms,alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 3carbon atoms, trifluoromethyl groups or hydroxy groups. The mostpreferred group is the benzyloxycarbonyl group, which may beunsubstituted or may have 1 or 2 substituents selected from the groupconsisting of fluorine atoms, chlorine atoms, methyl groups or methoxygroups.

Where substituent A is a monoalkylcarbamoyl group, the alkyl part hasfrom 1 to 6 carbon atoms, i.e. the group as a whole has from 2 to 7carbon atoms. The alkyl part may be a straight or branched chain groupand examples of such alkylcarbamoyl groups include the methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,isobutylcarbamoyl, sec-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyland 2,2-dimethylpropylcarbamoyl groups. Of these, we prefer thosealkylcarbamoyl groups having from 2 to 5 carbon atoms.

Where substituent A is a dialkylcarbamoyl group, each alkyl part hasfrom 1 to 4 carbon atoms, i.e. the group as a whole has from 3 to 9,preferably from 3 to 7, carbon atoms. The alkyl parts may each be astraight or branched chain group and the two alkyl groups may be thesame or different. Examples of such dialkylcarbamoyl groups include thedimethylcarbamoyl, diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,N-methyl-N-propylcarbamoyl, N-methyl-N-butylcarbamoyl,N-ethyl-N-propylcarbamoyl and N-ethyl-N-isopropylcarbamoyl groups. Ofthese, we prefer those alkylcarbamoyl groups having from 3 to 5 carbonatoms. The monoalkylcarbamoyl groups are preferred over thedialkylcarbamoyl groups.

Where substituent A is an acyloxy group, this is an aliphatic,carboxylic acyloxy group, which may be a straight or branched chaingroup having from 1 to 6 carbon atoms. Examples include the formyloxy,acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy and hexanoyloxy groups. Of these, we preferthose straight or branched chain acyloxy groups having 1 to 5 carbonatoms, and most prefer those acyloxy groups having from 1 to 3 carbonatoms.

Examples of the groups and atoms which may be included in substituents Bare as follows:

halogen atoms, for example, the fluorine, chlorine, bromine and iodineatoms, preferably the fluorine, chlorine and bromine atoms;

alkyl groups having from 1 to 4 carbon atoms, which may be straight orbranched chain groups, such as the methyl, ethyl, propyl, butyl,isopropyl and t-butyl groups;

alkoxy groups having from 1 to 3 carbon atoms, which may be straight orbranched chain groups, such as the methoxy, ethoxy, propoxy andisopropoxy groups;

the nitro group;

haloalkyl groups having from 1 to 4 carbon atoms, and preferably havingfrom 1 to 3 halogen atoms, which may be the same or different, such asthe trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl,dibromomethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,2-fluoroethyl, 2,2-dibromoethyl, 3-chloropropyl, 3,3,3-trifluoropropyland 4-fluorobutyl groups, of which we prefer alkyl groups having from 1to 3 carbon atoms which are substituted by from 1 to 3 halogen atoms(and, where there are 2 or 3 halogen atoms, these are the same), morepreferably the methyl or ethyl groups which are substituted by from 1 to3 fluorine or chlorine atoms; the most preferred specific groups are thetrifluoromethyl, trichloromethyl, difluoromethyl and 2-fluoroethylgroups, especially the trifluoromethyl group; and

the hydroxy group.

R² and R³ may be the same as each other or they may be different. WhereR² or R³ represents a halogen atom, this may be, for example, thefluorine, chlorine, bromine or iodine atom, preferably the fluorine,chlorine or bromine atom, more preferably the fluorine or chlorine atom.

Where R² or R³ represents an alkoxy group, this may be a straight orbranched chain alkoxy group having from 1 to 5, preferably from 1 to 3,carbon atoms, and examples include the methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy and pentyloxy groups. Of these, we preferthose alkoxy groups having from 1 to 3 carbon atoms, more preferably themethoxy and ethoxy groups.

Where R² or R³ represents an alkoxycarbonyl group having from 2 to 7carbon atoms, this may be a straight or branched chain alkoxycarbonylgroup and the alkoxy part contains from 1 to 6 carbon atoms. Examples ofsuch groups include the methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,2,2-dimethylpropoxycarbonyl and hexyloxycarbonyl groups. Of these, weprefer those straight or branched chain alkoxycarbonyl groups havingfrom 2 to 5 carbon atoms, and more prefer those alkoxycarbonyl groupshaving 2 or 3 carbon atoms, i.e. the methoxycarbonyl and ethoxycarbonylgroups.

Where R² or R³ represents an alkyl group having from 1 to 5 carbonatoms, this may be a straight or branched chain, and examples includethe methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl,sec-butyl, t-butyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl and 2,2-dimethylpropyl groups. Ofthese, we prefer those straight or branched chain alkyl groups havingfrom 1 to 4 carbon atoms, and more prefer those straight or branchedchain alkyl groups having from 1 to 3 carbon atoms.

Where R² or R³ represents a haloalkyl group having from 1 to 4 carbonatoms, this preferably has from 1 to 3 halogen atoms, which may be thesame or different, and examples of such groups include thetrifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl,dibromomethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,2-fluoroethyl, 2,2-dibromoethyl, 3-chloropropyl, 3,3,3-trifluoropropyland 4-fluorobutyl groups, of which we prefer alkyl groups having from 1to 3 carbon atoms which are substituted by from 1 to 3 halogen atoms(and, where there are 2 or 3 halogen atoms, these are the same), morepreferably the methyl or ethyl groups which are substituted by from 1 to3 fluorine or chlorine atoms; the most preferred specific groups are thetrifluoromethyl, trichloromethyl, difluoromethyl and 2-fluoroethylgroups, especially the trifluoromethyl group.

Where R² or R³ represents a substituted alkyl group having from 1 to 12carbon atoms, which group is substituted by at least one substituentselected from the group consisting of substituents A, defined andexemplified above, this may be any one of such groups exemplified abovein relation to the similar groups which may be represented by R¹.

Where R⁴ represents an alkoxy group having from 1 to 5 carbon atoms,this may be a straight or branched chain alkoxy group having from 1 to5, preferably from 1 to 3, carbon atoms, and examples include themethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and pentyloxygroups. Of these, we prefer those alkoxy groups having from 1 to 3carbon atoms, more preferably the methoxy and ethoxy groups.

Where R⁴ represents an alkyl group having from 1 to 5 carbon atoms, thismay be a straight or branched chain, and examples include the methyl,ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, t-butyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl and 2,2-dimethylpropyl groups. Of these, we preferthose straight or branched chain alkyl groups having from 1 to 4 carbonatoms, and more prefer those straight or branched chain alkyl groupshaving from 1 to 3 carbon atoms.

Where R⁴ represents an acyloxy group, this is an aliphatic, carboxylicacyloxy group, which may be a straight or branched chain group havingfrom 1 to 6 carbon atoms. Examples include the formyloxy, acetoxy,propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy,pivaloyloxy and hexanoyloxy groups. Of these, we prefer those acyloxygroups having 1 to 5 carbon atoms, and more prefer those acyloxy groupshaving from 1 to 3 carbon atoms. The most preferred acyloxy group is theacetoxy group.

Where R⁴ represents an aralkyloxy group, the aralkyl part is as definedabove, and the alkyl part may be as exemplified above in relation to thearalkyloxycarbonyl groups. Examples of unsubstituted aralkyloxy groupsinclude the benzyloxy, phenethyloxy, 1-phenylethoxy, 3-phenylpropoxy andnaphthylmethoxy groups. Examples of substituted aralkyloxy groupsinclude any of the unsubstituted groups exemplified above but which issubstituted by at least one of substituents B, and specific examples ofsuch substituted groups include the o-, m- or p-fluorobenzyloxy, o-, m-or p-chlorobenzyloxy, 2-, m- or p-methylbenzyloxy, o-, m- orp-methoxybenzyloxy, o-, m- or p-nitrobenzyloxy, o-, m- orp-trifluoromethylbenzyloxy, o-, m- or p-hydroxybenzyloxy,3,5-di-t-butyl-4-hydroxybenzyloxy and 3,4,5-trimethoxybenzyloxy groups.Of these, we prefer those aralkyloxy groups which are unsubstituted orwhich have from 1 to 3 substituents selected from the group consistingof halogen atoms, alkyl groups having 1 to 4 carbon atoms, alkoxy groupshaving 1 to 3 carbon atoms, trifluoromethyl groups or hydroxy groups.The most preferred group is the benzyloxy group, which is preferablyunsubstituted but which may have 1 or 2 substituents selected from thegroup consisting of fluorine atoms, chlorine atoms, methyl groups ormethoxy groups.

Where R⁴ represents an aryloxy group, the aryl part is as defined above.Examples of unsubstituted aryloxy groups include the phenyloxy and 1-and 2-naphthyloxy groups. Examples of substituted aryloxy groups includeany of the unsubstituted groups exemplified above but which issubstituted by at least one of substituents B, and specific examples ofsuch substituted groups include the o-, m- or p-fluorophenyloxy, o-, m-or p-chlorophenyloxy, o-, m- or p-methylphenyloxy, o-, m- orp-methoxyphenyloxy, o-, m- or p-nitrophenyloxy, o-, m- orp-trifluoromethylphenyloxy, o-, m- or p-hydroxyphenyloxy,3,5-di-t-butyl-4-hydroxyphenyloxy and 3,4,5-trimethoxyphenyloxy groups.Of these, we prefer those aryloxy groups which are unsubstituted orwhich have from 1 to 3 substituents selected from the group consistingof halogen atoms, alkyl groups having 1 to 4 carbon atoms, alkoxy groupshaving 1 to 3 carbon atoms, trifluoromethyl groups or hydroxy groups.The most preferred group is the phenyloxy group, which is preferablyunsubstituted but which may have 1 or 2 substituents selected from thegroup consisting of fluorine atoms, chlorine atoms, methyl groups ormethoxy groups.

Where R⁴ represents an aryl group, the aryl part is as defined above.Examples of unsubstituted aryl groups include the phenyl and 1- and2-naphthyl groups. Examples of substituted aryl groups include any ofthe unsubstituted groups exemplified above but which is substituted byat least one of substituents B, and specific examples of suchsubstituted groups include the o-, m- or p-fluorophenyl, o-, m- orp-chlorophenyl, o-, m- or p-methylphenyl, o-, m- or p-methoxyphenyl, o-,m- or p-nitrophenyl, o-, m- or p-trifluoromethylphenyl, o-, m- orp-hydroxyphenyl, 3,5-di-t-butyl-4-hydroxyphenyl and3,4,5-trimethoxyphenyl groups. Of these, we prefer those aryl groupswhich are unsubstituted or which have from 1 to 3 substituents selectedfrom the group consisting of halogen atoms, alkyl groups having 1 to 4carbon atoms, alkoxy groups having 1 to 3 carbon atoms, trifluoromethylgroups or hydroxy groups. The most preferred group is the phenyl group,which is preferably unsubstituted but which may have 1 or 2 substituentsselected from the group consisting of fluorine atoms, chlorine atoms,methyl groups or methoxy groups.

Where R⁴ represents a haloalkyl group having from 1 to 4 carbon atoms,this preferably has from 1 to 3 halogen atoms, which may be the same ordifferent, and examples of such groups include the trifluoromethyl,trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl,2,2-dibromoethyl, 3-chloropropyl, 3,3,3-trifluoropropyl and4-fluorobutyl groups, of which we prefer alkyl groups having from 1 to 3carbon atoms which are substituted by from 1 to 3 halogen atoms (and,where there are 2 or 3 halogen atoms, these are the same), morepreferably the methyl or ethyl groups which are substituted by from 1 to3 fluorine or chlorine atoms; the most preferred specific groups are thetrifluoromethyl, trichloromethyl, difluoromethyl and 2-fluoroethylgroups, especially the trifluoromethyl group.

Where R⁴ or R⁵ represents a halogen atom, this may be, for example, thefluorine, chlorine, bromine or iodine atom, preferably the fluorine,chlorine or bromine atom, more preferably the fluorine or chlorine atom.

Where R⁵ represents an alkoxy group, this may be a straight or branchedchain alkoxy group having from 1 to 5, preferably from 1 to 3, carbonatoms, and examples include the methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy and pentyloxy groups. Of these, we prefer those alkoxygroups having from 1 to 3 carbon atoms, more preferably the methoxygroup.

Where R⁵ represents an alkyl group having from 1 to 5 carbon atoms, thismay be a straight or branched chain, and examples include the methyl,ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, t-butyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl and 2,2-dimethylpropyl groups. Of these, we preferthose straight or branched chain alkyl groups having from 1 to 4 carbonatoms, and more prefer those straight or branched chain alkyl groupshaving from 1 to 3 carbon atoms.

Where R⁶ represents a halogen atom, this may be, for example, thefluorine, chlorine, bromine or iodine atom, preferably the fluorine,chlorine or bromine atom, more preferably the fluorine or chlorine atom.

Where R⁶ represents an alkoxy group, this may be a straight or branchedchain alkoxy group having from 1 to 5, preferably from 1 to 3, carbonatoms, and examples include the methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy and pentyloxy groups. Of these, we prefer those alkoxygroups having from 1 to 3 carbon atoms, more preferably the methoxygroup.

Where R⁶ represents an alkyl group having from 1 to 5 carbon atoms, thismay be a straight or branched chain, and examples include the methyl,ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, t-butyl,2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl and 2,2-dimethylpropyl groups. Of these, we preferthose straight or branched chain alkyl groups having from 1 to 4 carbonatoms, and more prefer those straight or branched chain alkyl groupshaving from 1 to 3 carbon atoms. The most preferred alkyl group is themethyl group.

A preferred class of compounds of the present invention is thosecompounds of formula (I) and salts thereof in which:

R⁰ represents a hydrogen atom, a methyl group or a hydroxymethyl group;

R¹ represents a substituted alkyl group having from 1 to 12 carbon atomsand substituted by at least 1 and no more than 8 substituents selectedfrom the group consisting of substituents A¹, defined below;

R² and R³ are the same or different and each represents a hydrogen atom,a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, amethoxy group, an ethoxy group, a carboxy group, an alkoxycarbonyl grouphaving from 2 to 7 carbon atoms, an alkyl group having from 1 to 5carbon atoms, a nitro group, a trifluoromethyl group or a substitutedalkyl group having from 1 to 12 carbon atoms and substituted by at least1 and no more than 8 substituents selected from the group consisting ofsubstituents A¹, defined below;

X represents an oxygen or sulfur atom;

Ar represents a group of formula (II) or (III), defined above;

R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group,an ethoxy group, an alkyl group having from 1 to 5 carbon atoms, anacetoxy group, a nitro group, a cyano group, a benzyloxy group, aphenoxy group, a phenyl group or a trifluoromethyl group;

R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a methoxy group, an alkyl group havingfrom 1 to 5 carbon atoms or a nitro group; and

R⁶ represents a hydrogen atom, a fluorine atom, a chlorine atom, ahydroxy group, a methoxy group or a methyl group; and

said substituents A¹ are selected from the group consisting of carboxygroups, alkoxycarbonyl groups having from 2 to 7 carbon atoms,aryloxycarbonyl groups in which the aryl part is as defined above,aralkyloxycarbonyl groups in which the aralkyl part is as defined above,mono- and di-alkylcarbamoyl groups having from 2 to 7 carbon atoms,carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, aliphaticcarboxylic acyloxy groups having from 1 to 6 carbon atoms and2,4-dioxothiazolidin-5-yl groups.

More preferred compounds of the present invention are those compounds offormula (I) in which:

R⁰ represents a hydrogen atom or a methyl group;

R¹ represents a substituted alkyl group which has from 1 to 12 carbonatoms and which is substituted by at least 1 and no more than 6substituents selected from the group consisting of substituents A²defined below;

R² represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a methoxy group, an ethoxy group, analkyl group having from 1 to 4 carbon atoms, a nitro group, or asubstituted alkyl group which has from 1 to 4 carbon atoms and which hasfrom 1 to 3 substituents selected from the group consisting of carboxygroups, alkoxycarbonyl groups having 2 or 3 carbon atoms,methylcarbamoyl groups, carbamoyl groups, hydroxy groups and aliphaticcarboxylic acyloxy groups having from 2 to 5 carbon atoms;

R³ represents a hydrogen atom, a fluorine atom, a chlorine atom, ahydroxy group, a methoxy group, a methyl group or a t-butyl group;

X represents an oxygen or sulfur atom; and

Ar represents a group of formula (II) or (III), defined above;

R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group,an ethoxy group, an alkyl group having from 1 to 4 carbon atoms, anacetoxy group, a nitro group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group;

R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a methoxy group or an alkyl group havingfrom 1 to 4 carbon atoms;

R⁶ represents a hydrogen atom, a fluorine atom, a chlorine atom, ahydroxy group, a methoxy group or a methyl group; and

said substituents A² are selected from the group consisting of:

carboxy groups,

alkoxycarbonyl groups having from 2 to 5 carbon atoms,

phenoxycarbonyl groups, which are unsubstituted or which are substitutedby from 1 to 3 substituents selected from the group consisting ofhalogen atoms,

alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from1 to 3 carbon atoms, nitro groups, trifluoromethyl groups and hydroxygroups,

benzyloxycarbonyl and phenethyloxycarbonyl groups, which areunsubstituted or which are substituted by from 1 to 3 substituentsselected from the group consisting of halogen atoms, alkyl groups havingfrom 1 to 4 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms,nitro groups, trifluoromethyl groups and hydroxy groups,

monoalkylcarbamoyl groups having from 2 to 4 carbon atoms,

carbamoyl groups,

hydroxycarbamoyl groups,

hydroxy groups,

aliphatic carboxylic acyloxy groups having from 1 to 6 carbon atoms, and

2,4-dioxothiazolidin-5-yl groups.

A still more preferred class of compounds of the present invention arethose compounds of formula (I) and salts thereof, in which:

R⁰ represents a hydrogen atom or a methyl group;

R¹ represents a substituted alkyl group which has from 1 to 6 carbonatoms and which is substituted by at least 1 and no more than 6substituents selected from the group consisting of substituents A³,defined below;

R² represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a methoxy group, an ethoxy group, analkyl group having from 1 to 4 carbon atoms, or a substituted alkylgroup which has from 1 to 3 carbon atoms and which is substituted byfrom 1 to 3 substituents selected from the group consisting of carboxygroups, alkoxycarbonyl groups having 2 or 3 carbon atoms,methylcarbamoyl groups, carbamoyl groups, hydroxy groups and aliphaticcarboxylic acyloxy groups having from 2 to 5 carbon atoms;

R³ represents a hydrogen atom, a fluorine atom, a chlorine atom, ahydroxy group, a methoxy group, a methyl group or a t-butyl group;

X represents an oxygen or sulfur atom;

Ar represents a group of formula (II) or (III), defined above;

R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group,an ethoxy group, an alkyl group having from 1 to 4 carbon atoms, anacetoxy group, a nitro group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group;

R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a methoxy group or an alkyl group havingfrom 1 to 4 carbon atoms;

R⁶ represents a hydrogen atom, a fluorine atom, a chlorine atom, ahydroxy group, a methoxy group or a methyl group; and

said substituents A³ are selected from the group consisting of:

carboxy groups,

alkoxycarbonyl groups having from 2 to 5 carbon atoms,

benzyloxycarbonyl and phenethyloxycarbonyl groups which areunsubstituted or which are substituted by from 1 to 3 substituentsselected from the group consisting of halogen atoms, alkyl groups havingfrom 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms,nitro groups, trifluoromethyl groups and hydroxy groups,

monoalkylcarbamoyl groups having from 2 to 4 carbon atoms,

carbamoyl groups,

hydroxycarbamoyl groups,

hydroxy groups

aliphatic carboxylic acyloxy groups having from 1 to 6 carbon atoms, and

2,4-dioxothiazolidin-5-yl groups.

Still more preferred compounds of the present invention are thosecompounds of formula (I) in which:

R⁰ represents a hydrogen atom or a methyl group;

R¹ represents a substituted alkyl group which has from 1 to 3 carbonatoms and which is substituted by at least 1 and no more than 4substituents selected from the group consisting of substituents A⁴,defined below;

R² represents a hydrogen atom, a fluorine atom, a chlorine atom, ahydroxy group, a methoxy group, an alkyl group having from 1 to 4 carbonatoms or a hydroxymethyl group;

R³ represents a hydrogen atom, a chlorine atom, a hydroxy group, amethoxy group or a methyl group;

X represents an oxygen atom;

Ar represents a group of formula (II) or (III), defined above;

R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group,an ethoxy group, an alkyl group having from 1 to 4 carbon atoms, anacetoxy group, a nitro group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group;

R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a methoxy group or an alkyl group havingfrom 1 to 4 carbon atoms;

R⁶ represents a hydrogen atom, a fluorine atom, a chlorine atom, ahydroxy group, a methoxy group or a methyl group; and

said substituents A⁴ are selected from the group consisting of:

carboxy groups,

alkoxycarbonyl group having from 2 to 5 carbon atoms,

benzyloxycarbonyl groups which are unsubstituted or which aresubstituted by from 1 to 3 substituents selected from the groupconsisting of alkyl groups having from 1 to 4 carbon atoms and hydroxygroups, monoalkylcarbamoyl groups having from 2 to 4 carbon atoms,

carbamoyl groups,

hydroxycarbamoyl groups,

hydroxy groups,

aliphatic carboxylic acyloxy groups having from 1 to 6 carbon atoms, and

2,4-dioxothiazolidin-5-yl groups;

Still more preferred compounds of the present invention are-thosecompounds of formula (I) in which:

R⁰ represents a hydrogen atom or a methyl group;

R¹ represents a substituted alkyl group which has from 1 to 3 carbonatoms and which is substituted by at least 1 and no more than 4substituents selected from the group consisting of substituents A⁵,defined below;

R² represents a hydrogen atom, a chlorine atom, a hydroxy group, amethoxy group, a methyl group or a hydroxymethyl group;

R³ represents a hydrogen atom or a methyl group;

X represents an oxygen atom;

Ar represents a group of formula (II) or (III), defined above;

R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group,an ethoxy group, an alkyl group having from 1 to 4 carbon atoms, anacetoxy group, a nitro group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group;

R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a hydroxy group, a methoxy group or an alkyl group havingfrom 1 to 4 carbon atoms;

R⁶ represents a hydrogen atom, a hydroxy group, a methoxy group or amethyl group; and

said substituents A⁵ are selected from the group consisting of:

carboxy groups,

alkoxycarbonyl group having from 2 to 4 carbon atoms,

benzyloxycarbonyl groups which are unsubstituted or which aresubstituted by from 1 to 3 substituents selected from the groupconsisting of alkyl groups having from 1 to 4 carbon atoms and hydroxygroups,

monoalkylcarbamoyl groups having 2 or 3 carbon atoms,

carbamoyl groups,

hydroxycarbamoyl groups,

hydroxy groups,

aliphatic carboxylic acyloxy groups having from 2 to 5 carbon atoms, and

2,4-dioxothiazolidin-5-yl groups.

Still more preferred compounds of the present invention are thosecompounds of formula (I) in which:

R⁰ represents a hydrogen atom;

R¹ represents a substituted alkyl group which has from 1 to 3 carbonatoms and which is substituted by at least 1 and no more than 4substituents selected from the group consisting of substituents A⁶,defined below;

R² represents a hydrogen atom, a chlorine atom, a hydroxy group, amethoxy group, a methyl group or a hydroxymethyl group;

R³ represents a hydrogen atom;

X represents an oxygen atom;

Ar represents a group of formula (II) or (III), defined above;

R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, a methoxy group, an alkyl group having from 1 to 4 carbonatoms, a phenoxy group or a trifluoromethyl group;

R⁵ represents a hydrogen atom, a chlorine atom, a methoxy group or analkyl group having from 1 to 4 carbon atoms;

R⁶ represents a hydrogen atom, a hydroxy group or a methoxy group; and

said substituents A⁶ are selected from the group consisting of:

carboxy groups,

alkoxycarbonyl groups having from 2 to 4 carbon atoms,

monoalkylcarbamoyl groups having 2 or 3 carbon atoms, carbamoyl groups,

hydroxycarbamoyl groups,

hydroxy groups,

aliphatic carboxylic acyloxy groups having from 2 to 5 carbon atoms, and

2,4-dioxothiazolidin-5-yl groups;

Still more preferred compounds of the present invention are thosecompounds of formula (I) in which:

R⁰ represents a hydrogen atom;

R¹ represents an alkyl group which has from 1 to 3 carbon atoms andwhich is substituted by 1 or 2 substituents selected from the groupconsisting of substituents A⁷, defined below;

R² represents a hydrogen atom, a chlorine atom, a hydroxy group or ahydroxymethyl group;

R³ represents a hydrogen atom;

X represents an oxygen atom;

Ar represents a phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-bromophenyl, 3-fluorophenyl, 3-phenoxyphenyl, 3-methylphenyl,3-methoxyphenyl, 3,5-dichlorophenyl, 3,5-di-t-butyl-4-hydroxyphenyl,3,4,5-trimethoxyphenyl, 3-trifluoromethylphenyl,3-chloro-4-fluorophenyl, 1-naphthyl or 2-naphthyl group; and

said substituents A⁷ are selected from the group consisting ofalkoxycarbonyl group having from 2 to 4 carbon atoms, hydroxy groups,aliphatic carboxylic acyloxy groups having from 2 to 5 carbon atoms and2,4-dioxothiazolidin-5-yl groups.

Still more preferred compounds of the present invention are thosecompounds of formula (I) in which:

R⁰ represents a hydrogen atom;

R¹ represents a methoxycarbonylmethyl, ethoxycarbonylmethyl,2-methoxycarbonylethyl, bis(methoxycarbonyl)methyl, hydroxymethyl,2-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxy-2-propyl,1-methoxycarbonyl-1-hydroxymethyl, 2-methoxycarbonyl-2-hydroxyethyl,2-acetyloxyethyl or 2,4-dioxothiazolidin-5-ylmethyl group;

R² represents a hydrogen atom, a chlorine atom or a hydroxymethyl group;

R³ represents a hydrogen atom;

X represents an oxygen atom; and

Ar represents a phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-bromophenyl, 3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl,3,5-di-t-butyl-4-hydroxyphenyl, 3-trifluoromethylphenyl,3-chloro-4-fluorophenyl or 2-naphthyl group.

The most preferred compounds of the present invention are thosecompounds of formula (I) in which:

R⁰ represents a hydrogen atom;

R¹ represents a methoxycarbonylmethyl, ethoxycarbonylmethyl,2-methoxycarbonylethyl, bis(methoxycarbonyl)methyl, hydroxymethyl,2-hydroxyethyl, 2-methoxycarbonyl-2-hydroxyethyl or2,4-dioxothiazolidin-5-yl-methyl group;

R² represents a hydrogen atom;

R³ represents a hydrogen atom;

X represents an oxygen atom; and

Ar represents a phenyl, 3-chlorophenyl, 3-bromophenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl or 2-naphthyl group.

The compounds of the present invention can exist in the form of variousstereoisomers, as shown in formula (IV): ##STR7## in which R⁰, R¹, R²,R³, X and Ar are as defined above. Where R⁰ represents a hydrogen atom,there are at least two asymmetric carbon atoms (marked *1 and *3) and,where R⁰ represents a methyl or hydroxymethyl group, there are at leastthree asymmetric carbon atoms (marked *1, *2 and *3). Although these areall represented herein by a single molecular formula, the presentinvention includes both the individual, isolated isomers and mixtures(where the amounts of isomers may be equal or different), includingracemates thereof. Where stereospecific synthesis techniques areemployed or optically active compounds are employed as startingmaterials, individual isomers may be prepared directly; on the otherhand, if a mixture of isomers is prepared, the individual isomers may beobtained by conventional resolution techniques.

Of the compounds of the invention, we prefer those isomers in which theasymmetric carbon atoms marked by *1 and *3 are in the R-configuration.

Examples of specific compounds of the invention are those compounds offormula (I-1), in which the various substituent groups are as defined inTable 1, and formula (I-2), in which the various substituent groups areas defined in Tables 2 to 8. ##STR8##

In the Tables, the following abbreviations are used:

    ______________________________________                                        Ac               acetyl                                                       Boc              butoxycarbonyl                                               iBoc             isobutoxycarbonyl                                            sBoc             sec-butoxycarbonyl                                           tBoc             t-butoxycarbonyl                                             Bu               butyl                                                        tBu              t-butyl                                                      Byr              butyryl                                                      iByr             isobutyryl                                                   Bzc              benzyloxycarbonyl                                            Et               ethyl                                                        Etc              ethoxycarbonyl                                               Me               methyl                                                       Mec              methoxycarbonyl                                              Np               naphthyl                                                     Ph               phenyl                                                       Piv              pivaloyl                                                     Pr               propyl                                                       iPr              isopropyl                                                    iPrc             isopropoxycarbonyl                                           Prn              propionyl                                                    Tfm              trifluoromethyl                                              Thiz             thiazolidin-5-yl                                             Val              valeryl                                                      iVal             isovaleryl                                                   ______________________________________                                    

                                      TABLE 1                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              Ar     R.sup.0                                                                             R.sup.1     R.sup.2                                                                              R.sup.3                                    __________________________________________________________________________    1-1                                                                              Ph     --CH.sub.2 OH                                                                       4-HOOCCH.sub.2 --                                                                         H      H                                          1-2                                                                              3-ClPh Me    4-MecCH.sub.2 --                                                                          H      H                                          1-3                                                                              3-ClPh H     4-MecCH.sub.2 --                                                                          H      H                                          1-4                                                                              3-ClPh H     4-EtcCH.sub.2 --                                                                          H      H                                          1-5                                                                              3-ClPh H     4-Mec.sub.2 CH--                                                                          H      H                                          1-6                                                                              3-ClPh H     4-BzcCH.sub.2 --                                                                          H      H                                          1-7                                                                              3-ClPh H     4-(2,2-diEtcEt)--                                                                         H      H                                          1-8                                                                              3-ClPh H     4-HOCH.sub.2 --                                                                           H      H                                          1-9                                                                              3-ClPh H     4-HOCH.sub.2 --                                                                           3-HOCH.sub.2 --                                                                      H                                          1-10                                                                             3-ClPh H     4-(2-HOEt)--                                                                              H      H                                          1-11                                                                             3-ClPh H     4-(3-HOPr)--                                                                              H      H                                          1-12                                                                             3-ClPh H     4-(2-AcOEt)--                                                                             H      H                                          1-13                                                                             3-ClPh H     4-(HOCH.sub.2).sub.2 CH--                                                                 H      H                                          1-14                                                                             3-FPh  H     4-MecCH.sub.2 --                                                                          H      H                                          1-15                                                                             3-TfmPh                                                                              H     4-MecCH.sub.2 --                                                                          H      H                                          1-16                                                                             3-BrPh H     4-MecCH.sub.2 --                                                                          H      H                                          1-17                                                                             3,5-ditBu-                                                                           H     4-MecCH.sub.2 --                                                                          H      H                                             4-HOPh                                                                     1-18                                                                             3-Cl-4-FPh                                                                           H     4-(Mec)(HO)CH--                                                                           H      H                                          1-19                                                                             3,5-diClPh                                                                           H     4-(Mec-HOCH)CH.sub.2 --                                                                   H      H                                          1-20                                                                             2-Np   H     4-MecCH.sub.2 --                                                                          H      H                                          1-21                                                                             3-ClPh H     4-(2-PivOEt)--                                                                            H      H                                          __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Cpd.                                                                          No.   Ar        R.sup.0                                                                             R.sup.1        R.sup.2                                                                            R.sup.3                             ______________________________________                                        2-1   3-ClPh    H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-2   3-Cl-4-FPh                                                                              H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-3   3-ClPh    H     4-(2-HOOCEt)-- H    H                                   2-4   3-FPh     H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-5   3-BrPh    H     4-(HOOC)--(HO)CH--                                                                           H    H                                   2-6   3-TfmPh   H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-7   3-MePh    H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-8   4-ClPh    H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-9   2-ClPh    H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-10  2-Np      H     4-HOOCCH.sub.2 --                                                                            H    H                                   2-11  3-ClPh    H     4-(HOOC)--(HO)CH--                                                                           H    H                                   2-12  3-ClPh    H     4-HOOCCH.sub.2 --                                                                            2-Cl H                                   ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              Ar      R.sup.0                                                                             R.sup.1       R.sup.2                                                                              R.sup.3                                 __________________________________________________________________________    3-1                                                                              3-ClPh  H     4-MecCH.sub.2 --                                                                            H      H                                       3-2                                                                              3-ClPh  H     3-MecCH.sub.2 --                                                                            H      H                                       3-3                                                                              3-ClPh  H     2-MecCH.sub.2 --                                                                            H      H                                       3-4                                                                              3-ClPh  H     4-(2-MecEt)-- H      H                                       3-5                                                                              Ph      H     4-(2-MecEt)-- H      H                                       3-6                                                                              Ph      --CH.sub.2 OH                                                                       4-MecCH.sub.2 --                                                                            H      H                                       3-7                                                                              2-Np    H     4-MecCH.sub.2 --                                                                            H      H                                       3-8                                                                              1-Np    H     4-MecCH.sub.2 --                                                                            H      H                                       3-9                                                                              Ph      Me    4-MecCH.sub.2 --                                                                            H      H                                       3-10                                                                             3-ClPh  H     3-MecCH.sub.2 --                                                                            4-MecCH.sub.2 --                                                                     H                                       3-11                                                                             2-ClPh  H     4-MecCH.sub.2 --                                                                            H      H                                       3-12                                                                             4-ClPh  H     4-MecCH.sub.2 --                                                                            H      H                                       3-13                                                                             3-FPh   H     4-MecCH.sub.2 --                                                                            H      H                                       3-14                                                                             3-BrPh  H     4-MecCH.sub.2 --                                                                            H      H                                       3-15                                                                             3,5-diClPh                                                                            H     4-MecCH.sub.2 --                                                                            H      H                                       3-16                                                                             3,4,5-triMeOPh                                                                        H     4-MecCH.sub.2 --                                                                            H      H                                       3-17                                                                             3,4,5-triMeOPh                                                                        H     4-(2,2-diEtcEt)--                                                                           H      H                                       3-18                                                                             3-ClPh  H     4-Mec.sub.2 CH--                                                                            H      H                                       3-19                                                                             3-ClPh  H     4-EtcCH.sub.2 --                                                                            H      H                                       3-20                                                                             3-ClPh  H     4-iPrcCH.sub.2 --                                                                           H      H                                       3-21                                                                             3-ClPh  H     4-BocCH.sub.2 --                                                                            H      H                                       3-22                                                                             3-ClPh  H     4-[1,1,2,2-(Etc).sub.4 Et]--                                                                H      H                                       3-23                                                                             3-ClPh  H     4-MecCH.sub.2 --                                                                            2-HO   H                                       3-24                                                                             3-ClPh  H     4-MecCH.sub.2 --                                                                            2-HO   2-H                                     3-25                                                                             3-Clph  H     3-MecCH.sub.2 --                                                                            4-HO   H                                       3-26                                                                             3-PhOPh H     4-MecCH.sub.2 --                                                                            H      H                                       3-27                                                                             3,5-ditBu-                                                                            H     4-MecCH.sub.2 --                                                                            H      H                                       4-HOPh                                                                        3-28                                                                             3-ClPh  H     4-MecCH.sub.2 --                                                                            2-Cl   H                                       3-29                                                                             Ph      H     4-MecCH.sub.2 --                                                                            H      H                                       3-30                                                                             3,5-ditBu-                                                                            H     5-EtcCH.sub.2 --                                                                            2-HO   H                                       4-HOPh                                                                        3-31                                                                             3-ClPh  H     2-MecCH.sub.2 --                                                                            5-MecCH.sub.2 --                                                                     4-HO                                    3-32                                                                             2,5-diClPh                                                                            H     4-MecCH.sub.2 --                                                                            2-HO   H                                       3-33                                                                             3,5-ditBu-                                                                            H     4-MecCH.sub.2 --                                                                            2-F    H                                       4-HOPh                                                                        3-34                                                                             3-ClPh  H     4-MecCH.sub.2 --                                                                            2-MeO  H                                       3-35                                                                             3,5-ditBu-                                                                            H     5-MecCH.sub.2 --                                                                            2-MeO  H                                       4-HOPh                                                                        3-36                                                                             3,5-diMe-                                                                             H     5-BocCH.sub.2 --                                                                            2-EtO  H                                       4-HOPh                                                                        3-37                                                                             3-ClPh  H     4-MecCH.sub.2 --                                                                            2-MeO  6-MeO                                   3-38                                                                             3-ClPh  H     4-iPrcCH.sub.2 --                                                                           2-EtO  H                                       3-39                                                                             3-ClPh  H     4-EtcCH.sub.2 --                                                                            2-Me   H                                       3-40                                                                             2-F-4-BrPh                                                                            H     4-Mec.sub.2 CH--                                                                            H      H                                       3-41                                                                             3-Cl-4-FPh                                                                            H     4-MecCH.sub.2 --                                                                            H      H                                       3-42                                                                             3-TfmPh H     4-Bzc.sub.2 CH--                                                                            H      H                                       3-43                                                                             3,4-diClPh                                                                            H     4-[3,5-ditBu-4-HOBzc)CH.sub.2 --                                                            H      H                                       3-44                                                                             3-TfmPh H     4-EtcCH.sub.2 --                                                                            3-EtcCH.sub.2 --                                                                     H                                       3-45                                                                             3-ClPh  H     4-iBocCH.sub.2 --                                                                           H      H                                       3-46                                                                             3-ClPh  H     4-sBocCH.sub.2 --                                                                           H      H                                       3-47                                                                             3-ClPh  H     4-tBocCH.sub.2 --                                                                           H      H                                       3-48                                                                             3-ClPh  H     4-iPrc.sub.2 CH--                                                                           H      H                                       3-49                                                                             3-ClPh  H     4-(2,2-diMecEt)--                                                                           H      H                                       3-50                                                                             3-ClPh  H     4-(Mec)(Me)CH--                                                                             H      H                                       3-51                                                                             3-BrPh  H     4-[1,1,2,2-(Etc).sub.4 Et]--                                                                H      H                                       3-52                                                                             3-ClPh  H     4-PhOCOCH.sub.2 --                                                                          H      H                                       3-53                                                                             Ph      Me    4-(3-F-PhOCO)CH.sub.2 --                                                                    H      H                                       3-54                                                                             3-ClPh  H     4-(PhOCO).sub.2 CH--                                                                        H      H                                       3-55                                                                             3-ClPh  H     4-(4-MeOBzc).sub.2 CH--                                                                     H      H                                       3-56                                                                             2-Np    H     4-[(2-PhEtc)CH.sub.2 ]--                                                                    H      H                                       3-57                                                                             3-Cl--Ph                                                                              H     4-(3,5-ditBu-4-HOBzc)CH.sub.2 --                                                            H      H                                       3-58                                                                             3-ClPh  H     4-Bzc.sub.2 CH--                                                                            H      H                                       3-59                                                                             3-FPh   H     4-(2,2-diBzcEt)--                                                                           H      H                                       3-60                                                                             Ph      H     3-MecCH.sub.2 --                                                                            4-HO   H                                       3-61                                                                             3-MePh  H     4-MecCH.sub.2 --                                                                            H      H                                       3-62                                                                             3-MeOPh H     4-MecCH.sub.2 --                                                                            H      H                                       3-63                                                                             3,5-diClPh                                                                            H     4-MecCH.sub.2 --                                                                            H      H                                       3-64                                                                             2-Np    H     4-Mec.sub.2 CH--                                                                            H      H                                       3-65                                                                             3-TfmPh H     3-MecCH.sub.2 --                                                                            4-HO   H                                       3-66                                                                             3-TfmPh H     4-MecCH.sub.2 --                                                                            H      H                                       __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                        Cpd.                                                                          No.   Ar        R.sup.0                                                                             R.sup.1        R.sup.2                                                                             R.sup.3                            ______________________________________                                        4-1   3-ClPh    H     4-HOHNCOCH.sub.2 --                                                                          H     H                                  4-2   3-ClPh    H     4-H.sub.2 NCOCH.sub.2 --                                                                     H     H                                  4-3   3-ClPh    H     4-MeHNCOCH.sub.2 --                                                                          H     H                                  4-4   3-ClPh    H     4-BuHNCOCH.sub.2 --                                                                          H     H                                  4-5   3-ClPh    H     4-Et.sub.2 NCOCH.sub.2 --                                                                    H     H                                  4-6   3-ClPh    H     4-H.sub.2 NCOCH.sub.2 --                                                                     2-Cl  H                                  4-7   3-ClPh    H     4-(2-H.sub.2 NCOEt)--                                                                        H     H                                  4-8   3-ClPh    H     4-EtHNCOCH.sub.2 --                                                                          H     H                                  4-9   2-Np      H     4-PrHNCOCH.sub.2 --                                                                          H     H                                  4-10  3-BrPh    H     4-iPrHNCOCH.sub.2 --                                                                         H     H                                  4-11  3-ClPh    H     4-(H.sub.2 NCO).sub.2 CH--                                                                   H     H                                  4-12  3-ClPh    H     4-[2,2-di(H.sub.2 NCO)Et)--                                                                  H     H                                  4-13  2-Np      H     4-(H.sub.2 NCO).sub.2 CH--                                                                   H     H                                  4-14  3,5-ditBu-                                                                              H     4-(H.sub.2 NCO).sub.2 CH--                                                                   H     H                                  4-HOPh                                                                        4-15  3-ClPh    H     4-HOHNCOCH.sub.2 --                                                                          2-Cl  H                                  4-16  3-FPh     H     4-iPrHNCOCH.sub.2 --                                                                         H     H                                  4-17  3-TfmPh   H     4-H.sub.2 NCOCH.sub.2 --                                                                     H     H                                  4-18  3-MeOPh   H     4-H.sub.2 NCOCH.sub.2 --                                                                     H     H                                  ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Cpd.                                                                          No.  Ar        R.sup.0   R.sup.1       R.sup.2                                                                           R.sup.3                            ______________________________________                                        5-1  3-ClPh    H         4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  5-2  2-Np      H         4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  5-3  3-TfmPh   H         4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  5-4  3-Cl-4-FPh                                                                              H         4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  5-5  3,5-ditBu-                                                                              H         4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  4-HOPh                                                                        5-6  3-MeOPh   H         4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  5-7  Ph        Me        4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  5-8  Ph        --CH.sub.2 OH                                                                           4-(2,4-dioxoThiz)CH.sub.2 --                                                                H   H                                  ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Cpd.                                                                          No.  Ar          R.sup.0                                                                             R.sup.1         R.sup.2                                                                           R.sup.3                            ______________________________________                                        6-1  3-ClPh      H     4-(Mec)(HO)CH-- H   H                                  6-2  3-ClPh      H     4-(2-Mec-2-HOEt)--                                                                            H   H                                  6-3  3,5-diMeOPh H     4-(H.sub.2 NCO)(HO)CH--                                                                       H   H                                  6-4  3-F-4-MeOPh H     4-(3-F-PhOCO)(HO)CH--                                                                         H   H                                  6-5  3,5-diMe-   H     4-(Mec)(HO)CH-- H   H                                  4-HOPh                                                                        6-6  1-HO-4-Br-  H     4-(2-Etc-1-HOEt)--                                                                            H   H                                  2-Np--                                                                        6-7  3-ClPh      H     4-(HOOC)(HO)CH--                                                                              H   H                                  6-8  3-ClPh      H     4-(3-HOOC-2-HOPr)--                                                                           H   H                                  6-9  3-ClPh      H     4-(H.sub.2 NCO)(HO)CH--                                                                       H   H                                  6-10 2-Np        H     4-(iPrc)(HO)CH--                                                                              H   H                                  6-11 3-ClPh      H     4-(Etc)(HO)CH-- H   H                                  6-12 3-ClPh      H     4-(2-Etc-1-HOEt)--                                                                            H   H                                  6-13 3-ClPh      H     4-(4-TfmPhOCO)(HO)CH--                                                                        H   H                                  6-14 3-FPh       H     4-(PhOCO)(HO)CH--                                                                             H   H                                  6-15 3-ClPh      H     4-(PhOCO)(HO)CHCH.sub.2 --                                                                    H   H                                  6-16 3-ClPh      H     4-(2-PhOCO-2-AcOEt)--                                                                         H   H                                  6-17 3-ClPh      H     4-(2-H.sub.2 NCO-2-HOEt)--                                                                    H   H                                  6-18 3,4,5-triMeO--                                                                            H     4-(2-MeHNCO-2-HOEt)--                                                                         H   H                                       --Ph                                                                     6-19 3-ClPh      H     4-(2-H.sub.2 NCO-2-AcOEt)--                                                                   H   H                                  6-20 3-TfmPh     H     4-(Mec)(HO)CH-- H   H                                  ______________________________________                                    

                                      TABLE 7                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              Ar      R.sup.0                                                                          R.sup.1     R.sup.2 R.sup.3                                     __________________________________________________________________________    7-1                                                                              Ph      H  4-(2-HOEt)--                                                                              H       H                                           7-2                                                                              3-ClPh  H  4-HOCH.sub.2 --                                                                           H       H                                           7-3                                                                              3-ClPh  H  4-(2-HOEt)--                                                                              H       H                                           7-4                                                                              3-ClPh  H  4-(3-HOPr)--                                                                              H       H                                           7-5                                                                              3-ClPh  H  4-(1,2-diHOEt)--                                                                          H       H                                           7-6                                                                              3-Clph  H  4-(2,3-diHOPr)--                                                                          H       H                                           7-7                                                                              3-ClPh  H  4-HOCH.sub.2 --                                                                           3-HOCH.sub.2 --                                                                       H                                           7-8                                                                              3-ClPh  H  4-HOCH.sub.2 --                                                                           2-HOCH.sub.2 --                                                                       H                                           7-9                                                                              3-ClPh  H  4-[1,1,2,2-tetra-                                                                         H       H                                                         (HOCH.sub.2)Et]--                                               7-10                                                                             3-ClPh  H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-11                                                                             3-ClPh  H  4-[2,2-di(HOCH.sub.2)Et]--                                                                H       H                                           7-12                                                                             3-Clph  H  4-(1-HOEt)--                                                                              H       H                                           7-13                                                                             3-Clph  H  4-(2-HOEt)--                                                                              3-(2-HOEt)--                                                                          H                                           7-14                                                                             3-ClPh  H  4-HOCH.sub.2 --                                                                           3-Tfm   H                                           7-15                                                                             3-FPh   H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-16                                                                             4-MePh  H  4-(1,2-diHOEt)--                                                                          H       H                                           7-17                                                                             2-Np    H  4-(2-HOPr)--                                                                              H       H                                           7-18                                                                             2-Np    H  4-(1-HOEt)--                                                                              H       H                                           7-19                                                                             4-MeONp H  4-(2,3-diHOPr)--                                                                          H       H                                           7-20                                                                             3,5-ditBu-                                                                            H  4-(2-HOEt)--                                                                              H       H                                           4-HOPh                                                                        7-21                                                                             3-ClPh  H  4-(2-HOEt)--                                                                              2-Cl    H                                           7-22                                                                             3-ClPh  H  4-(2-HOEt)--                                                                              2-HO    H                                           7-23                                                                             3-TfmPh H  4-(2-HOEt)--                                                                              H       H                                           7-24                                                                             3-FPh   H  4-(2-HOEt)--                                                                              H       H                                           7-25                                                                             3-MePh  H  4-(2-HOEt)--                                                                              H       H                                           7-26                                                                             3-MeOPh H  4-(2-HOEt)--                                                                              H       H                                           7-27                                                                             2-Np    H  4-(2-HOEt)--                                                                              H       H                                           7-28                                                                             3-Cl-4-FPh                                                                            H  4-(2-HOEt)--                                                                              H       H                                           7-29                                                                             3-BrPh  H  4-(2-HOEt)--                                                                              H       H                                           7-30                                                                             2-Np    H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-31                                                                             1-Np    H  4-(2-HOEt)--                                                                              H       H                                           7-32                                                                             3,4,5-triMeO--                                                                        H  4-(2-HOEt)--                                                                              H       H                                              --Ph                                                                       7-33                                                                             3-ClPh  H  4-HO        3-(2-HOEt)--                                                                          H                                           7-34                                                                             3-ClPh  H  4-HOCH.sub.2 --                                                                           2-Me    6-Me                                        7-35                                                                             3-ClPh  H  4-(2-HOPr)--                                                                              H       H                                           7-36                                                                             2-Np    H  4-(1,2-diHOEt)--                                                                          H       H                                           7-37                                                                             3-TfmPh H  4-(1,2-diHOEt)--                                                                          H       H                                           7-38                                                                             3,5-ditBu-                                                                            H  4-(1,2-diHOEt)--                                                                          H       H                                           4-HOPh                                                                        7-39                                                                             3,5-diClPh                                                                            H  4-(1,2-diHOEt)--                                                                          H       H                                           7-40                                                                             2-Np    H  4-(2,3-diHOPr)--                                                                          H       H                                           7-41                                                                             3,4-diClPh                                                                            H  4-(2,3-diHOPr)--                                                                          H       H                                           7-42                                                                             3-TfmPh H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-43                                                                             Ph      Me 4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-44                                                                             3,5-diClPh                                                                            H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-45                                                                             3,4-diClPh                                                                            H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-46                                                                             3,5-diMe-                                                                             H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           4-HOPh                                                                        7-47                                                                             3,4,5-triMeO--                                                                        H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                              --Ph                                                                       7-48                                                                             3-Cl-4-FPh                                                                            H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-49                                                                             2-F-4-BrPh                                                                            H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-50                                                                             Ph      H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-51                                                                             3-PhOPh H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           7-52                                                                             3,5-ditBu-                                                                            H  4-(HOCH.sub.2).sub.2 CH--                                                                 H       H                                           4-HOPh                                                                        7-53                                                                             2-Np    H  4-[2,2-di(HOCH.sub.2)Et]--                                                                H       H                                           7-54                                                                             3,4-diClPh                                                                            H  4-[2,2-di(HOCH.sub.2)Et]--                                                                H       H                                           7-55                                                                             3,5-diClPh                                                                            H  4-[2,2-di(HOCH.sub.2)Et]--                                                                H       H                                           __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________    Cpd.                                                                          No. Ar      R.sup.0                                                                           R.sup.1      R.sup.2                                                                           R.sup.3                                      __________________________________________________________________________    8-1 3-ClPh  H   4-(2-AcOEt)--                                                                              H   H                                            8-2 3-ClPh  H   4-(2-PivOEt)--                                                                             H   H                                            8-3 3-MeOPh H   4-(AcOCH.sub.2).sub.2 CH--                                                                 H   H                                            8-4 3-ClPh  H   4-AcOCH.sub.2 --                                                                           H   H                                            8-5 3-FPh   H   4-PrnOCH.sub.2 --                                                                          2-Me                                                                              6-Me                                         8-6 3,4,5-triMeO--                                                                        H   4-ByrOCH.sub.2 --                                                                          H   H                                                --Ph                                                                      8-7 3-ClPh  H   4-iByrOCH.sub.2 --                                                                         H   H                                            8-8 3-ClPh  H   4-(2-PrnOEt)--                                                                             H   H                                            8-9 3-ClPh  H   4-(2-ByrOEt)--                                                                             H   H                                            8-10                                                                              3-ClPh  H   4-(2-iByrOEt)--                                                                            H   H                                            8-11                                                                              3,4-diClPh                                                                            H   4-(2-ValOEt)--                                                                             H   H                                            8-12                                                                              3,5-diClPh                                                                            H   4-(2-iValOEt)--                                                                            H   H                                            8-13                                                                              2-Np    H   4-(2-PivOEt)--                                                                             H   H                                            8-14                                                                              3-TfmPh H   4-(1-AcOEt)--                                                                              H   H                                            8-15                                                                              Ph      Me  4-(2-AcOEt)--                                                                              H   H                                            8-16                                                                              3-ClPh  H   4-(1,2-diAcOEt)--                                                                          H   H                                            8-17                                                                              2-Np    H   4-(1,2-diAcOEt)--                                                                          H   H                                            8-18                                                                              3-ClPh  H   4-(2-AcO-1-HOEt)--                                                                         H   H                                            8-19                                                                              3-Cl-4-FPh                                                                            H   4-(2,3-diAcOPr)--                                                                          H   H                                            8-20                                                                              3-ClPh  H   4-(AcOCH.sub.2).sub.2 CH--                                                                 H   H                                            8-21                                                                              2-Np    H   4-(PivOCH.sub.2).sub.2 CH--                                                                H   H                                            8-22                                                                              3-ClPh  H   4-[2,2-di(AcOCH.sub.2)Et]--                                                                H   H                                            8-23                                                                              3-Cl-4-FPh                                                                            H   4-(2-AcO-1-HOEt)--                                                                         H   H                                            __________________________________________________________________________

Of the compounds listed above, preferred compounds are Compounds No.:

3-1.2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol;

3-5.2-{2-[4-(2-Methoxycarbonylethyl)phenoxy]-1-methylethyl}amino-1-phenylethanol;

3-14.2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-bromophenyl)ethanol;

3-15.2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-dichlorophenyl)ethanol;

3-29.2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-phenylethanol;

3-41.2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-chloro-4-fluorophenyl)ethanol;

3-62.2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-methoxyphenyl)ethanol;

3-66.2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-trifluoromethylphenyl)ethanol;

5-1.5-[4-{2-[2-(3-Chlorophenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione;

5-3.5-[4-{2-[2-(3-Trifluoromethylphenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione;

6-1.2-{2-[4-(α-Methoxycarbonyl-α-hydroxymethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol;

6-2.2-{2-[4-(2-Methoxycarbonyl-2-hydroxyethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol;

7-2.2-[2-(4-Hydroxymethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol;

7-3.2-{2-[4-(2-Hydroxyethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol;

7-4. 2-{2-[4-(3-Hydroxypropyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl) ethanol;

and salts thereof.

The most preferred compounds are Compounds No.:

3-1, 3-14, 3-29, 3-41, 3-66, 5-1, 5-3, 6-2 and 7-3 and salts thereof.

The compounds of the present invention can be prepared by a variety ofwell known processes which are known per se. For example, in generalterms, they may be prepared by reacting a compound of formula (V):##STR9## (in which Ar and R⁰ are as defined above; Z represents ahydrogen atom or a hydroxy-protecting group; and W represents an oxygenatom, or it represents a hydrogen atom on one bond of the associatedcarbon atom and an amino group or a halogen atom on the other bond ofthe associated carbon atom) or an epoxide corresponding to said compoundof formula (V) where W represents a hydrogen atom and a halogen atomwith a compound of formula (VI): ##STR10## (in which X, R¹, R² and R³are as defined above; and, where W represents said hydrogen atom andsaid halogen atom or W represents said oxygen atom, W' represents ahydrogen atom on one bond of the associated carbon atom and an aminogroup on the other bond of the associated carbon atom, or, where Wrepresents said hydrogen atom and said amino group, W' represents anoxygen atom);

and, if necessary, reducing the resulting compound;

and, if necessary, removing any protecting group;

and optionally salifying any resulting compound.

As explained in more detail below, in Method 1, where W represents ahydrogen atom and an amino group, and W' represents an oxygen atom, theproduct of the reaction of the compounds of formula (V) and (VI)contains a double bond and is reduced to give the compound of formula(I). The epoxide corresponding to the compound of formula (V) where Wrepresents a hydrogen atom and a halogen atom can be treated inessentially the same way as that compound where W represents a hydrogenatom and a halogen atom, also as explained in greater detail hereafter,in Method 3.

Specific examples of processes which can be used to prepare thecompounds of the present invention are shown in the following Methods 1to 6.

METHOD 1

In this Method, an amino-alcohol of formula (VII): ##STR11## (in whichR⁰ and Ar are as defined above) [vide, for example, D. T. Collins, J.Med. Chem., 13, 674-680 (1970)] is reacted with a keto compound offormula (VIII): ##STR12## (in which R¹, R², R³ and X are as definedabove), to give a compound of formula (IX): ##STR13## (in which R⁰, R¹,R², R³, X and Ar are as defined above) [Step A] and then the resultingcompound is reduced [Step B].

The compound of formula (VIII) can be prepared by conventional means,for example by reacting a haloacetone with a phenol or thiophenolcompound, using methods well known in the art.

In Step A of this reaction, a compound of formula (IX) is prepared byreacting an amino-alcohol of formula (VII) with a keto compound offormula (VIII). The reaction may be carried out in the presence orabsence of a dehydrating agent, such as anhydrous sodium carbonate,anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrouscalcium chloride, anhydrous magnesium sulfate or a dehydrating molecularsieve.

In general, the reaction is preferably carried out in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include:hydrocarbons, which may be aliphatic or aromatic, such as benzene,toluene, xylene, hexane and heptane; halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as chloroform,methylene chloride and carbon tetrachloride; ethers, such as diethylether, tetrahydrofuran and dioxane; amides, such as dimethylformamide,dimethylacetamide, hexamethylphosphoric triamide; alcohols, such asmethanol and ethanol; sulfoxides, such as dimethyl sulfoxide; sulfolane;and mixtures of any two or more of the solvents described above.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from ice-cooling to the boiling point of thesolvent used. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, in most cases where the reaction iscarried out under the preferred conditions outlined above, a period offrom 0.5 to 10 hours will suffice.

The reaction is preferably carried out in the presence of a solvent,such as a hydrocarbon or an alcohol, for a period of from 1 to 5 hoursat a temperature from ice-cooling to the reflux temperature. Morepreferably the reaction is carried out in benzene by heating underreflux for a period of from 1 to 3 hours and removing the resultingwater.

In Step B, a compound of formula (I) is prepared by reducing thecompound of formula (IX), which may have been prepared as described inStep A. The reaction is normally carried out by using a reducing agentor by hydrogenation in the presence of a catalyst. Where reduction iscarried out using a reducing agent, the nature of the reducing agentused is not critical to the present invention, and any reducing agentcommonly used in reactions of this type may equally be used here.Examples of suitable reducing agents include: metal hydrides, such aslithium borohydride, sodium borohydride, sodium cyanoborohydride,lithium aluminum hydride or diisobutylaluminum hydride. In general, thereaction is preferably carried out in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: hydrocarbons, whichmay be aliphatic or aromatic, such as benzene, toluene, xylene, hexaneor heptane; ethers, such as diethyl ether, tetrahydrofuran or dioxane;amides, such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; alcohols, such as methanol, ethanol orisopropanol; and mixtures of any two or more of the solvents describedabove.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at anytemperature from ice-cooling to heating, for example to 50° C. or more.The time required for the reaction may likewise vary widely, dependingon many factors, notably the reaction temperature and the nature of thereagents. However, in most cases, a period of from 0.5 hour to severaldays will normally suffice.

The reaction is preferably carried out using sodium borohydride orsodium cyanoborohydride in the presence of an alcoholic solvent, and ata temperature of from ice-cooling to 50° C. for a period of from 1 to 24hours.

Where reduction is carried out by hydrogenation in the presence ofcatalyst, the catalyst used may be any catalyst commonly used forcatalytic reduction, and the nature of the catalyst is not critical tothe present invention. Examples of preferred catalysts includepalladium-on-charcoal or platinum oxide. In general, the reaction ispreferably carried out in the presence of a solvent, the nature of whichis not critical, provided that it has no adverse effect upon thereaction and that it can dissolve the reagents, at least to some extent.Examples of suitable solvents include: ethers, such as diethyl ether,tetrahydrofuran or dioxane; amides, such as dimethylformamide ordimethylacetamide; alcohols, such as methanol, ethanol or isopropanol;esters, such as methyl acetate or ethyl acetate; and mixtures of any twoor more of the solvents described above. Where a palladium catalyst isused, the catalytic hydrogenation is preferably carried out under frommedium to high pressure, preferably at from 1 to 5 kg/cm². Where aplatinum catalyst is used, the hydrogenation is preferably carried outat atmospheric pressure. The reaction will take place over a wide rangeof temperatures, and the precise reaction temperature chosen is notcritical to the invention. In general, we find it convenient to carryout the reaction at a temperature in the range of from room temperatureto 50° C. It is also preferably carried out in the presence of analcoholic solvent, particularly methanol or ethanol.

Where the compound of formula (VII) is an optically active compoundowing to the presence of asymmetric carbon atoms at the positions markedby *1 and/or *2, the stereochemical integrity can be retained in thecompound of formula (IX) and thus the compound of formula (I), soproduced. Moreover, in Step B, where a conventional asymmetrichydrogenation reaction can be carried out, compounds of formula (I) canbe prepared as a stereoisomer having an asymmetric carbon atom at theposition marked by *3.

METHOD 2

In this Method, a compound of formula (I) is prepared by reacting ahalohydrin of general formula (X): ##STR14## (in which R⁰ and Ar are asdefined above and Hal represents a halogen atom, such as a chlorine orbromine atom) with an amine of formula (XI): ##STR15## (in which R¹, R²,R³ and X are as defined above).

The reaction may be carried out in the presence or absence of adeacidifying agent, which may be a base, such as sodium carbonate,sodium hydrogencarbonate, potassium carbonate or triethylamine. Also, itis preferably carried out in the presence of a solvent, the nature ofwhich is not critical, provided that it has no adverse effect upon thereaction and that it can dissolve the reagents, at least to some extent.Examples of suitable solvents include: hydrocarbons, which may bealiphatic or aromatic, such as benzene, toluene, xylene, hexane orheptane; halogenated hydrocarbons, especially halogenated aliphatichydrocarbons, such as chloroform, methylene chloride or carbontetrachloride; ethers, such as diethyl ether, tetrahydrofuran ordioxane; amides, such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; alcohols, such as methanol, ethanol orisopropanol; sulfoxides, such as dimethyl sulfoxide; and mixtures of thesolvents described above.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at anytemperature from room temperature to the reflux temperature of thereaction medium. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, in most cases, a period of from 1hour to several days will normally suffice. The reaction is preferablycarried out in the presence of a solvent, such as an alcohol, an amideor a sulfoxide, at a temperature from room temperature to 60° C., andfor a period of from 3 hours to 3 days.

Compounds of formula (XI) can be prepared by the procedure summarized inthe following reaction scheme A: ##STR16##

In the above formulae, R¹, R², R³ and X are as defined above; Z¹represents an amino-protecting group, for example an alkoxycarbonylgroup or an aryloxycarbonyl group, which may be as defined andexemplified in relation to the similar groups which may be included insubstituents A above, such as a t-butoxycarbonyl group or abenzyloxycarbonyl group; and Z² represents a sulfonyl group, such as analkanesulfonyl group in which the alkyl moiety preferably has from 1 to4 carbon atoms, or an arylsulfonyl group in which the aryl part may beas previously defined and exemplified, for example a mesyl(methanesulfonyl) group or a tosyl (toluenesulfonyl, preferablyp-toluenesulfonyl) group.

In step 1 of this reaction scheme, a compound of formula (c) is preparedby reacting an N-protected amino-alcohol of formula (a) with a phenylcompound of formula (b). This reaction may be carried out byconventional procedures, for example using the Mitsunobu reaction [O.Mitsunobu, Synthesis, 1 (1981)]. In general, the reaction is normallyand preferably effected in the presence of a solvent. There is noparticular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or on thereagents involved and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: hydrocarbons, whichmay be aliphatic or aromatic, such as benzene, toluene, xylene, hexaneor heptane; halogenated hydrocarbons, especially halogenated aliphatichydrocarbons, such as chloroform, methylene chloride or carbontetrachloride; ethers, such as diethyl ether, tetrahydrofuran ordioxane; amides, such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; and mixtures of any two or more of thesolvents described above. The reaction can take place over a wide rangeof temperatures, and the precise reaction temperature is not critical tothe invention. In general, we find it convenient to carry out thereaction at a temperature of from that of an ice-water bath to someheating, more preferably from ice-cooling to 60° C. The time requiredfor the reaction may also vary widely, depending on many factors,notably the reaction temperature and the nature of the reagents andsolvent employed. However, provided that the reaction is effected underthe preferred conditions outlined above, a period of from several hoursto several days, more preferably from 5 hours to 3 days, will usuallysuffice.

A compound of formula (c) can also be prepared, as shown by step 2, byreacting a compound of formula (d) with a compound of formula (e). Thereaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include:hydrocarbons, which may be aliphatic or aromatic, such as benzene,toluene, xylene, hexane or heptane; ethers, such as diethyl ether,tetrahydrofuran or dioxane; amides, such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; and mixtures of anytwo or more of the solvents described above. The reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature of from that of an ice-waterbath to some heating, more preferably from ice-cooling to 60° C. Thetime required for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of the reagentsand solvent employed. However, provided that the reaction is effectedunder the preferred conditions outlined above, a period of from 1 hourto several days, more preferably from 1 to 24 hours, will usuallysuffice. The reaction is preferably carried out in the presence of asolvent at a temperature of from ice-cooling to 60° C. for a period offrom 1 to 24 hours.

A compound of formula (d) can be prepared, as shown in step 3, byprotecting the amino group, for example by mesylation or tosylation, ofa compound of formula (a). The reaction may be carried out in thepresence or absence of a deacidifying agent, such as sodium carbonate,sodium hydrogencarbonate, potassium carbonate, triethylamine orpyridine, and preferably in the presence of a solvent. There is noparticular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or on thereagents involved and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: hydrocarbons, whichmay be aliphatic or aromatic, such as benzene, toluene, xylene, hexaneor heptane; halogenated hydrocarbons, especially halogenated aliphatichydrocarbons, such as chloroform, methylene chloride or carbontetrachloride; ethers, such as diethyl ether, tetrahydrofuran ordioxane; amides, such as dimethylformamide, dimethylacetamide orhexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide;and mixtures of any two or more of the solvents described above. Thereaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from that of an ice-water bath to some heating, morepreferably from ice-cooling to 60° C. The time required for the reactionmay also vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents and solvent employed.However, provided that the reaction is effected under the preferredconditions outlined above, a period of from 1 hour to several days, morepreferably from 1 to 24 hours, will usually suffice. The reaction ispreferably carried out in the presence of triethylamine at a temperatureof from ice-cooling to 60° C. for a period of from 1 to 24 hours.

A compound of formula (XI) can then be prepared, as shown in step 4, byremoving the amino-protecting groups, such as the t-butoxycarbonyl orbenzyloxycarbonyl groups, from the compound of formula (c) byconventional means (for example, as described in T. W. Green,"Protective Groups in Organic Synthesis", John Wiley & Sons; and J. F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press).

Optically active compounds of formula (XI) can be prepared by using anoptically active compound of formula (a) as the starting material.

Where the compounds of formulae (X) and (XI) are optically active,reacting them together will give the respective stereoisomers owing tothe asymmetric carbon atoms at the positions marked by *1, *2 and *3 asshown in formulae (IV), (X) and (XI).

METHOD 3

A compound of formula (I) can be prepared by reacting an epoxidizedcompound of formula (XII): ##STR17## (in which R⁰ and Ar are as definedabove) with an amino compound of formula (XI): ##STR18## (in which R¹,R² and X are as defined above).

The reaction may be carried out in the presence or absence of an acidcatalyst, such as hydrogen chloride, sulfuric acid, boron trifluoride oraluminum chloride, or of basic alumina and preferably in the presence ofa solvent. There is no particular restriction on the nature of thesolvent to be employed, provided that it has no adverse effect on thereaction or on the reagents involved and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: hydrocarbons, which may be aliphatic or aromatic, such asbenzene, toluene, xylene, hexane or heptane; halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as chloroform,methylene chloride or carbon tetrachloride; ethers, such as diethylether, tetrahydrofuran or dioxane; amides, such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; alcohols, such asmethanol, ethanol or isopropanol; sulfoxides, such as dimethylsulfoxide; nitriles, such as acetonitrile; water; and mixtures of anytwo or more of the solvents described above. The reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature of from that of an ice-waterbath to some heating, more preferably from ice-cooling to 120° C. Thetime required for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of the reagentsand solvent employed. However, provided that the reaction is effectedunder the preferred conditions outlined above, a period of from 1 hourto several days, more preferably from 1 to 24 hours, will usuallysuffice. The reaction is preferably carried out in the presence of asolvent at a temperature of from 30° C. to 120° C. for a period of from1 to 24 hours.

Where the compounds of formulae (XI) and (XII) are optically active,reaction of these two compounds may yield the respective stereoisomersof the compound of formula (I) owing to the asymmetric carbon atoms atthe positions marked by *1, *2 and *3 as shown in formulae (IV), (XI)and (XII).

METHOD 4

A compound of formula (I) can be prepared by [Step A1] reacting acarbonyl compound of formula (XIII): ##STR19## (in which R⁰ and Ar areas defined above and Z³ represents a hydrogen atom or ahydroxy-protecting group) with an amino compound of formula (XI), asshown above, to produce a compound of formula (XIV): ##STR20## (inwhich, R⁰, R¹, R², R³, X, Ar and Z³ are as defined above) and then [StepB1] reducing the resulting compound of formula (XIV) to produce acompound of formula (XV): ##STR21## (in which, R⁰, R¹, R², R³, X, Ar andZ³ are as defined above) and then, if necessary, deprotecting thecompound where Z³ represents a hydroxy-protecting group, to give acompound of formula (I).

Step A1 and B1 are essentially the same as, and may be carried out undersimilar conditions to, those described in Steps A and B of Method 1.

The nature of the hydroxy-protecting group represented by Z³ is notcritical to the present invention, and any such group which mayconventionally be used as a hydroxy-protecting group, may equally beused in the present reaction. Examples of such groups include thetetrahydropyranyl, methoxymethyl, diphenylmethyl, trityl,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups.Following Steps A1 and B1, if the protecting group needs to be removed,the nature of the removal reaction will depend on the nature of theprotecting group, as is well known in the art, and the reactionsemployed are also well known. Examples of such removal reactions aregiven in T. W. Green, "Protective Groups in Organic Synthesis", JohnWiley & Sons; and J. F. W. McOmie, "Protective Groups in OrganicChemistry", Plenum Press, the disclosures of which are incorporatedherein by reference.

Those compounds of formula (XIII) in which R⁰ represents a hydrogenatom, that is compounds of formula (XVI): ##STR22## can be prepared bythe procedure summarized in the following reaction scheme B: ##STR23##

In the above formulae, Ar and Z³ are as defined above and R represents alower alkyl group, preferably having from 1 to 4 carbon atoms, forexample as exemplified in relation to substituents B, above.

In step 1 of this reaction scheme, a compound of formula (f) is treatedby conventional means, for example, as described in Organic Syntheses I,pp. 336, the disclosure of which is incorporated herein by reference, togive a compound of formula (g).

The reaction is normally carried out by reacting the compound of formula(f) with hydrogen cyanide or with trimethylsilyl cyanide in the presenceof zinc iodide, and in the presence or absence of a solvent, to preparea cyanohydrin derivative, and then subjecting the resulting cyanohydrincompound to hydrolysis catalyzed by an acid. The reaction for formingthe cyanohydrin compound is normally carried out over a wide range oftemperatures, for example from ice-cooling to heating, preferably at atemperature of from room temperature to 100° C. Hydrolysis catalyzed byan acid is normally carried out using a conventional acid, for example,an inorganic acid, such as hydrochloric acid or sulfuric acid, or anorganic acid, such as p-toluenesulfonic acid or acetic acid, in thepresence of an excess of water at a temperature of from room temperatureto the reflux temperature of the reaction mixture for a period of fromseveral tens of minutes to several tens of hours. The reaction ispreferably carried out by heating under reflux in the presence ofhydrochloric acid or sulfuric acid for a period of from 30 minutes to 10hours.

Subsequently, esterification of the compound of formula (g) thusobtained can be effected by acid-catalyzed esterification or bytreatment with an esterifying agent, such as a diazoalkane or an alkylhalide plus alkali, to produce a compound of formula (h).

Acid-catalyzed esterification may be effected by reacting the compoundof formula (g) with, for example, an excess of an alcohol, in thepresence or absence of a solvent, and preferably in the presence of aninorganic acid, such as hydrogen chloride or sulfuric acid, or anorganic acid, such as p-toluenesulfonic acid, at a suitable temperature,for example from room temperature to heating, for a suitable period, forexample from several hours to several days.

Esterification using a diazoalkane is preferably effected in thepresence of a solvent, for example: an alcohol, such as methanol orethanol; a hydrocarbon, which may be aliphatic or aromatic, such asbenzene, toluene, xylene, hexane or heptane; an ether, such as diethylether, tetrahydrofuran or dioxane; or a mixture of any two or more ofthe solvents described above. The reaction can take place over a widerange of temperatures, and the precise reaction temperature is notcritical to the invention. In general, we find it convenient to carryout the reaction at a temperature of from ice-cooling to heating, morepreferably at a temperature of from ice-cooling to 60° C. The timerequired for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of the reagentsand solvent employed.

In an esterification reaction using an alkali and an alkyl halide,examples of the alkali which may be used include alkali metalcarbonates, such as potassium carbonate or sodium carbonate. Thereaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: alcohols,such as methanol or ethanol; ethers, such as diethyl ether,tetrahydrofuran or dioxane; hydrocarbons, such as benzene, toluene,xylene, hexane or heptane; amides, such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; and mixtures of anytwo or more of the solvents described above. The reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature of from about room temperatureto heating. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from several hours to several days will usually suffice.

In step 3, the compound of formula (h) thus obtained is protected usinga conventional hydroxy-protecting group to produce a compound of formula(i). Examples of the hydroxy-protecting groups which may be usedinclude: tetrahydropyranyl, methoxymethyl, diphenylmethyl, trityl,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups,for example, as described in T. W. Green, "Protective Groups in OrganicSyntheses", John Wiley & Sons; and J. F. W. McOmie, "Protective Groupsin Organic Chemistry", Plenum Press.

In step 4, the compound of formula (XVI) can then be prepared byconventional means from the compound (i), for example, by reacting thecompound of formula (i) with diisobutylaluminum hydride in a hydrocarbonsolvent such as hexane, heptane, benzene toluene or xylene, which hasbeen precooled in an acetone-dry ice-bath.

The compound of formula (XVI) can also be prepared by the proceduresummarized in the following reaction scheme C: ##STR24## (in which Ar,Z³ and R are as defined above).

In step 1 of this reaction scheme, a compound of formula (i) is reactedby conventional means with, for example, a metal hydride, such aslithium aluminum hydride or diisobutylaluminum hydride, to produce acompound of formula (j).

The reaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include ethers, suchas diethyl ether, tetrahydrofuran and dioxane.

The compound of formula (j) thus obtained is then oxidized in step 2 byconventional means, for example, using a sulfur trioxide/pyridinecomplex or a chromium oxidizing agent or by subjecting it to a Swernoxidation reaction to produce the compound of formula (XVI).

Where the compound of formula (XVI) is optically active, it is possibleto obtain stereoisomers of the compound formula (IV) having anasymmetric carbon atom at the position marked by *1. That is, where theamino compound of formula (XIV) is optically active and R⁰ represents ahydrogen atom, there can be separately prepared compounds of formula(IV) having stereochemistry made up of any desired combination of (*1R,*3R), (*1R, *3S), (*1S, *3R) or (*1S, *3S).

Moreover, a compound of formula (g) can be resolved into (R) and (S)compounds using any optically active amine which can be used forconventional optical resolution, for example, (+)- or (-)-ephedrine or(d)- or (l)-1-phenylethylamine.

METHOD 5

A compound wherein R¹, R² or R³ represents a hydroxyalkyl group can beprepared by reducing a corresponding compound wherein R¹, R² or R³represents an alkoxycarbonyl group. The reaction is normally carried outusing a reducing agent. Examples of the reducing agents which may beused include: metal hydrides, such as lithium borohydride, sodiumborohydride, sodium cyanoborohydride, lithium aluminum hydride ordiisobutylaluminum hydride. The reaction is normally and preferablyeffected in the presence of a solvent. There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or on the reagents involved andthat it can dissolve the reagents, at least to some extent. Examples ofsuitable solvents include: hydrocarbons, which may be aliphatic oraromatic, such as benzene, toluene, xylene, hexane or heptane; ethers,such as diethyl ether, tetrahydrofuran or dioxane; amides, such asdimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;alcohols such as methanol, ethanol or isopropanol; and mixtures of anytwo or more of the solvents described above. The reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature of from ice-cooling to heating,for example at or up to the reflux temperature of the reaction mixture.The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thereagents and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of from0.5 hour to several days will usually suffice. The reaction ispreferably carried out using sodium borohydride or lithium borohydridein the presence of an alcoholic solvent at a temperature of fromice-cooling to the reflux temperature of the reaction mixture for aperiod of from 1 to 24 hours. Alternatively, the reaction is alsopreferably carried out using lithium aluminum hydride in the presence ofan ether solvent at a temperature of from ice-cooling to the refluxtemperature of the reaction mixture for a period of from 1 to 24 hours.

METHOD 6

A compound corresponding to a compound of formula (I) but in which thesubstituted alkyl group represented by R¹, and optionally by R² and/orR³, is replaced by a substituted alkenyl group can be converted to thecorresponding compound of formula (I) by catalytic hydrogenation.

The catalyst used may be any catalyst commonly used for catalyticreduction, and the nature of the catalyst is not critical to the presentinvention. Examples of preferred catalysts include palladium-on-charcoalor platinum oxide. In general, the reaction is preferably carried out inthe presence of a solvent, the nature of which is not critical, providedthat it has no adverse effect upon the reaction and that it can dissolvethe compound to be reduced, at least to some extent. Examples ofsuitable solvents include: ethers, such as diethyl ether,tetrahydrofuran or dioxane; amides, such as dimethylformamide ordimethylacetamide; alcohols, such as methanol, ethanol or isopropanol;esters, such as methyl acetate or ethyl acetate; and mixtures of any twoor more of the solvents described above. Where a palladium catalyst isused, the catalytic hydrogenation is preferably carried out under frommedium to high pressure, preferably at from 1 to 5 kg/cm². Where aplatinum catalyst is used, the hydrogenation is preferably carried outat atmospheric pressure. The reaction will take place over a wide rangeof temperatures, and the precise reaction temperature chosen is notcritical to the invention. In general, we find it convenient to carryout the reaction at a temperature in the range of from room temperatureto 50° C. It is also preferably carried out in the presence of analcoholic solvent, particularly methanol or ethanol.

The desired compounds obtained by any of Methods 1 through 6 can berecovered from the reaction mixture by conventional means aftercompletion of the reaction. The compounds thus obtained can, if desired,be further purified by standard techniques, for example, by the variouschromatography techniques, notably column chromatography, and/or byrecrystallization, reprecipitation or the like. One suitable recoveryand purification technique comprises: adding a suitable solvent to thereaction mixture; extracting the product into the solvent; removing thesolvent by distillation from the extract; and purifying the residue bycolumn chromatography through silica gel or the like to afford thedesired compound in a pure state.

BIOLOGICAL ACTIVITY

The compounds of formula (I) and their pharmaceutically acceptable saltshave a variety of valuable physiological activities, which render themof great potential for the treatment or prophylaxis of a variety ofphysiological disorders. For example, they improve hyperglycemia,increase glucose tolerance which may have been impaired in obesity, theyinhibit the activity of aldose reductase, and improve hepaticgluconeogenesis and hyperlipemia; they are useful as preventive and/ortherapeutic agents for hyperglycemia, obesity, hyperlipemia and suchdiabetic complications as retinopathy, nephropathy, neuropathy,cataracts, coronary heart diseases and arteriosclerosis; they are alsouseful for the treatment and prevention of obesity-related hypertensionand osteoporosis. In addition, since the compounds of the presentinvention have a very low toxicity, they are useful as a preventiveand/or therapeutic agents for the diseases and disorders mentionedabove.

The biological activities of the compounds of the present invention areillustrated in the following Experiments, in which the compounds of theinvention are identified by the number of the one of the followingExamples in which its preparation is described.

EXPERIMENT 1 Hypoglycemic Effect during Glucose Load

The hypoglycemic effect of the compounds of the present invention duringglucose load in mice was measured as follows.

Three month old KK male mice, each weighing 28 to 30 g, were fastedovernight, and then 1 mg/kg of the compound to be tested orcarboxymethylcellulose (CMC) as a control was administered orally. After60 minutes, 1.2 g/kg of D-glucose was administered subcutaneously. Then,at 60 and 120 minutes after the subcutaneous glucose injection, bloodsamples were taken, and the glucose levels were determined by means of aglucose analyzer (GL-101, a product of Mitsubishi Kasei, Co.). Thehypoglycemic rates (R) of the test compound during the glucose load werecalculated according to the following equation:

    R=[1-(B/A)]×100

where

A: Blood glucose level in the group administered CMC

B: Blood glucose level in the group administered a test sample.

The results are shown in Table 9.

                  TABLE 9                                                         ______________________________________                                        Cpd. of          Number    Hypoglycemic rate during                           Example Dose     of        glucose load (%)                                   No.     (mg/kg)  mice      60 min.  120 min.                                  ______________________________________                                        3       1        4         67.3     56.5                                      6       1        4         43.4     40.5                                      8       1        4         56.8     45.1                                      24      1        4         61.4     56.9                                      27      1        4         68.4     52.1                                      40      1        4         37.9     24.5                                      41      1        4         50.1     43.0                                      42      1        4         60.9     57.6                                      43      1        4         66.5     58.6                                      44      1        4         38.1     24.8                                      47      1        4         60.9     51.5                                      ______________________________________                                    

As is clearly shown in Table 9, all of the tested compounds showed anexcellent hypoglycemic effect.

EXPERIMENT 2 Inhibition of Aldose Reductase

Bovine lens aldose reductase was separated and partially purified by themethod of S. Hyman and J. H. Kinoshita [J. Biol. Chem., 240, 877 (1965)]and K. Inagaki, I. Miwa and J. Okuda [Arch. Biochem. Biophys., 316, 337(1982)], and its activity was determined photometrically by the methodof Varma et al. [Biochem. Pharmac., 25, 2505 (1976)]. Inhibition ofenzyme activity was measured for the compounds of the present inventionat a concentration of 5 μg/ml, and the results are shown in thefollowing Table 10.

                  TABLE 10                                                        ______________________________________                                        Inhibition of Aldose reductase                                                Cpd. of       Inhibition (%)                                                                            IC.sub.50                                           Example No.   at 5 μg/ml                                                                             (μg/ml)                                          ______________________________________                                        34            63.3        2.5                                                 36            60.4        2.9                                                 48            47.5        --                                                  ______________________________________                                    

EXPERIMENT 3 Toxicity

The test animals employed were male mice of the ddY strain. The animalswere employed in groups of 3. The test compound was administered orallyto each animal group at a dose of 300 mg/kg body weight. The compoundsemployed were those prepared as described in Examples 1, 3, 8, 24, 47and 48. The animals were then observed for a period of one weekfollowing this administration, and, during the period of observation,they showed no abnormalities which could be attributed to the testcompounds. All animals were alive at the end of the period ofobservation.

In view of the substantial dose adminsitered to each animal, the zeromortality indicates that the compounds of the present invention have avery low toxicity.

The compounds of the present invention can be administered in variousforms, depending upon the patient and the desired route ofadministration. Suitable formulations for oral administration includetablets, capsules, granules, powders or syrups; and suitableformulations for parentheral administration include injections (whichmay be intravenous, intramuscular or subcutaneous), drops orsuppositories. These various preparations can be prepared byconventional means in which the active compound is mixed with any knownadditives commonly employed in the field of pharmaceutical preparations,such as vehicles, binders, disintegrators, lubricants, corrigents,solubilizers, suspending agents and coating agents. The dosage may bevaried depending on the symptoms, age and body weight of the patient,the route of administration and the form of the preparation. However, adaily dose of from 0.01 mg to 2,000 mg, which may be administered in asingle dose or in divided doses, is usually appropriate for an adulthuman patient.

The preparation of the compounds of the present invention is furtherillustrated by the following non-limiting Examples, and the preparationof certain of the starting materials is shown in the subsequentPreparations.

EXAMPLE 12-[2-(4-Hydroxymethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol1/6 ethyl acetate (Compound No. 7-2)

0.83 mg of lithium aluminum hydride was slowly added, with stirring, toa solution of 1.95 g of2-[2-(4-methoxycarbonylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(prepared as described in Preparation 1) dissolved in 70 ml oftetrahydrofuran, and the resulting mixture was allowed to react at roomtemperature for 2 hours. At the end of this time, 0.9 ml of water, 0.9ml of a 15% w/v aqueous solution of sodium hydroxide and 3 ml of waterwere added, in that order, to the reaction mixture, and the resultingmixture was stirred at room temperature. The reaction mixture was thenfiltered using a Celite (trade mark) filter aid, and the filtrate wasfreed from the solvent by distillation under reduced pressure. Theresulting residue was purified by column chromatography through silicagel, using a 10:1 by volume mixture of ethyl acetate and ethanol as theeluent, to give 1.5 g of the title compound as a glass-like material,having an Rf=0.55 (thin layer chromatography over silica gel, using a4:1 by volume mixture of ethyl acetate and ethanol as the developingsolvent).

The product contains some proportion of ethyl acetate but is not thoughtto be a complex.

EXAMPLE 25-[4-{2-[2-(3-Chlorophenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione1/2 ethyl acetate (Compound No. 5-1)

A solution of 2.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared asdescribed in Preparation 8) and 3.58 g of5-[4-(2-oxopropoxy)benzyl]thiazolidine -2,4-dione in 50 ml of benzenewas heated under reflux for 1.5 hours, whilst the water being formedduring the reaction was continuously removed. At the end of this time,the benzene used was removed by distillation under reduced pressure. Theresulting residue was dissolved in 100 ml of absolute methanol, and then3 g of sodium borohydride were added to the resulting solution. Thereaction mixture was allowed to stand overnight at room temperature,after which it was concentrated by evaporation under reduced pressure,and the concentrate was mixed with water. The resulting aqueous mixturewas extracted with ethyl acetate, and the extract was dried overanhydrous sodium sulfate. The solvent was removed by distillation underreduced pressure, and the resulting residue was purified by columnchromatography through silica gel, using ethyl acetate, followed by a10:1 by volume mixture of ethyl acetate and ethanol, as the eluent. Theproduct was recrystallized from ethyl acetate, to give 0.74 g of thetitle compound as crystals, melting at 100°-125° C.

EXAMPLE 32-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(Compound No. 3-1)

A solution of 2.2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared asdescribed in Preparation 8) and 2.6 g of methyl4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3)in 200 ml of benzene was heated under reflux for about 2 hours, whilstthe water being formed during the reaction was continuously removed. Atthe end of this time, the reaction mixture was freed from the benzeneused as solvent by distillation under reduced pressure, and theresulting residue was dissolved in 150 ml of absolute methanol. 1 g ofsodium borohydride was added to this solution, whilst ice-cooling, andthe resulting mixture was stirred at room temperature for 5 hours. Thereaction mixture was then mixed with ethyl acetate and with a saturatedaqueous solution of sodium chloride. The organic layer was separated andwas dried over anhydrous magnesium sulfate, and the solvent was removedby distillation under reduced pressure. The resulting residue waspurified by column chromatography through silica gel, using a 40:1:1 byvolume mixture of ethyl acetate, ethanol and triethylamine as theeluent, to give 2.3 g of the title compound having an Rf=0.44 (thinlayer chromatography over silica gel, using a 40:1:1 by volume mixtureof ethyl acetate, ethanol and triethylamine as the developing solvent).

EXAMPLE 4 2-{2-[4-(3-Hydroxypropyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl) ethanol (Compound No.7-4)

A procedure similar to that described in Example 2 was repeated, exceptthat 4.3 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as describedin Preparation 8), 3.5 g of methyl 3-[4-(2-oxopropoxy)phenyl]propionate(prepared as described in Preparation 5), 150 ml of benzene, 150 ml ofabsolute methanol and 6.12 g of sodium borohydride were used. A crudeproduct was obtained, and this was purified by column chromatographythrough silica gel, using a 10:1 by volume mixture of ethyl acetate andethanol as the eluent, to give 2.9 g of the title compound having anRf=0.40 (thin layer chromatography over silica gel, using a 10:1 byvolume mixture of ethyl acetate and ethanol as the developing solvent).

EXAMPLE 52-{2-[4-(2-Methoxycarbonylethyl)phenoxy]-1-methylethyl}amino-1-phenylethanol(Compound No. 3-5)

2.2 g of2-{2-[4-(2-methoxycarbonylethenyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(prepared as described in Preparation 53) were dissolved in 200 ml ofmethanol and hydrogenated by bubbling hydrogen through the solution atatmospheric pressure and at room temperature in the presence of 0.5 g of10% w/w palladium-on-charcoal for 3 hours. The catalyst was removed byfiltration, and the filtrate was concentrated by evaporation underreduced pressure. The concentrate was dissolved in ethyl acetate, andthe resulting solution was washed with an aqueous solution of potassiumcarbonate and with water, in that order, after which it was dried overanhydrous sodium sulfate. The solvent was then removed by distillationunder reduced pressure, and the residue was purified by columnchromatography through silica gel, using ethyl acetate as the eluent.The product thus obtained was recrystallized from a mixture of ethylacetate and hexane, to give 1.2 g of the title compound as crystals,melting at 103°-104° C.

EXAMPLE 62-{2-[4-(2-Methoxycarbonyl-2-hydroxyethyl)phenoxy]1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 6-2)

A mixture of 1.16 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared asdescribed in Preparation 8), 1.71 g of methyl3-[4-(2-oxopropoxy)phenyl]lactate (prepared as described in Preparation6) and 40 ml of benzene was heated under reflux for 3.5 hours, whilstthe water being formed during the reaction was continuously removed.After completion of the reaction, the benzene used in the reaction wasremoved by distillation under reduced pressure, and the residue wasdissolved in 50 ml of absolute methanol. 2.04 g of sodiumcyanoborohydride were added, whilst ice-cooling, to the solution, andthe resulting mixture was allowed to react overnight at roomtemperature. At the end of this time, methanol was removed bydistillation under reduced pressure, and the resulting residue was mixedwith ethyl acetate and with an aqueous solution of sodium chloride. Theethyl acetate layer was separated, washed with an aqueous solution ofsodium chloride and then dried over anhydrous sodium sulfate. Thesolvent was then removed by distillation under reduced pressure, and theresidue was purified by column chromatography through silica gel, usingethyl acetate as the eluent, to give 1.9 g of the title compound havingan Rf=0.30 (thin layer chromatography over silica gel, using ethylacetate as the developing solvent).

EXAMPLE 72-{2-[4-(2-Methoxycarbonylethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 3-4)

Following a procedure similar to that described in Example 6, but using4.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 3.5 g of methyl 3-[4-(2-oxopropoxy)phenyl]propionate(prepared as described in Preparation 5), 100 ml of benzene, 100 ml ofabsolute methanol and 2.6 g of sodium cyanoborohydride, 2.8 g of thetitle compound were obtained as crystals, melting at 65°-73° C.

EXAMPLE 82-{2-[4-(2-Hydroxyethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 7-3)

Following a procedure similar to that described in Example 2, but using2.0 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 2.13 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared asdescribed in Preparation 7), 100 ml of benzene, 100 ml of absolutemethanol and 0.95 g of sodium borohydride, a crude product was obtained.This product was purified first by column chromatography through silicagel, using a 20:1 by volume mixture of ethyl acetate and ethanol as theeluent, and then by recrystallization from ethyl acetate, to give 1.18 gand 1.02 g of two separate kinds of crystals, which are diastereomers ofthe title compound, melting at 108°-111° C. and at 78°-80° C.,respectively.

EXAMPLE 92-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-2(S)-hydroxymethyl-1(S)-phenylethanol(Compound No. 3-6)

Following a procedure similar to that described in Example 6, but using5.7 g of (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol, 5 g of methyl4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3),250 ml of benzene, 250 ml of absolute methanol and 4.34 g of sodiumcyanoborohydride, 1.54 g of the title compound were obtained having anRf=0.27 (thin layer chromatography over silica gel, using a 2:1 byvolume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 102-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(2-naphthyl)ethanol(Compound No. 3-7)

Following a procedure similar to that described in Example 6, but using3 g of 2-amino-1-(2-naphthyl)ethanol (prepared as described inPreparation 9), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (preparedas described in Preparation 3), 60 ml of benzene, 50 ml of absolutemethanol and 2.49 g of sodium cyanoborohydride, 3.23 g of the titlecompound were obtained having an Rf=0.15 (thin layer chromatography oversilica gel, using ethyl acetate as the developing solvent).

EXAMPLE 112-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(1-naphthyl)ethanol(Compound No. 3-8)

Following a procedure similar to that described in Example 6, but using3 g of 2-amino-1-(1-naphthyl)ethanol (prepared as described inPreparation 10), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 3), 60 ml of benzene, 50 ml ofabsolute methanol and 3 g of sodium cyanoborohydride, 1.9 g of the titlecompound were obtained having an Rf=0.35 (thin layer chromatography oversilica gel, using ethyl acetate as the developing solvent).

EXAMPLE 122-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-2(S)-methyl-1(R)-phenylethanol(Compound No. 3-9)

Following a procedure similar to that described in Example 6, but using3 g of (1R,2S)-(-)-norephedrine, 4.36 g of methyl4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3),60 ml of benzene, 50 ml of absolute methanol and 3.41 g of sodiumcyanoborohydride, 2.65 g of the title compound were obtained ascrystals, melting at 124° C. (after recrystallization from a mixture ofethyl acetate and hexane).

EXAMPLE 132-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-2(R)-methyl-1(S)-phenylethanol(Compound No. 3-9)

Following a procedure similar to that described in Example 12, but using3 g of (1S,2R)-(+)-1-norephedrine, 4.36 g of methyl4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3),60 ml of benzene, 50 ml of absolute methanol and 3.57 g of sodiumcyanoborohydride, 2.41 g of the title compound were obtained ascrystals, melting at 122° C.

EXAMPLE 142-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(2-chlorophenyl)ethanol(Compound No. 3-11)

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(2-chlorophenyl)ethanol (prepared as described inPreparation 11), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 3), 60 ml of benzene, 50 ml ofabsolute methanol and 2.3 g of sodium cyanoborohydride, 3.25 g of thetitle compound were obtained having an Rf=0.39 (thin layerchromatography over silica gel, using ethyl acetate as the developingsolvent).

EXAMPLE 152-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(4-chlorophenyl)ethanol(Compound No. 3-12)

Following a procedure similar to that described in Example 12, but using2 g of 2-amino-1-(4-chlorophenyl)ethanol (prepared as described inPreparation 12), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 3), 60 ml of benzene, 50 ml ofabsolute methanol and 2.7 g of sodium cyanoborohydride, 1.54 g of thetitle compound were obtained as crystals, melting at 78°-79° C.

EXAMPLE 162-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-fluorophenyl)ethanol(Compound No. 3-13)

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(3-fluorophenyl)ethanol (prepared as described inPreparation 13), 3.44 g of methyl 4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 3), 60 ml of benzene, 60 ml ofabsolute methanol and 3.6 g of sodium cyanoborohydride, 1.18 g of thetitle compound were obtained as crystals, melting at 52° C.

EXAMPLE 172-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,4,5-trimethoxyphenyl)ethanol(Compound No. 3-16)

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol (prepared as describedin Preparation 14), 2.35 g of methyl 4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 3), 70 ml of benzene, 60 ml ofabsolute methanol and 4.8 g of sodium cyanoborohydride, 3.14 g of thetitle compound were obtained having an Rf=0.21 (thin layerchromatography over silica gel, using ethyl acetate as the developingsolvent).

EXAMPLE 182-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-phenoxyphenyl)ethanol(Compound No. 3-26)

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(3-phenoxyphenyl)ethanol (prepared as described inPreparation 15), 3.4 g of methyl 4-(2-oxopropoxy)phenylacetate (preparedas described in Preparation 3), 70 ml of benzene, 60 ml of absolutemethanol and 3.7 g of sodium cyanoborohydride, 1.27 g of the titlecompound were obtained having an Rf=0.26 (thin layer chromatography oversilica gel, using ethyl acetate as the developing solvent).

EXAMPLE 192-{2-[4-(2-Hydroxyethyl)phenoxy]-1-methylethyl}amino-1(S)-phenylethanol(Compound No. 7-1)

A procedure similar to that described in Example 3 was repeated, exceptthat 1.4 g of 2-amino-1(S)-phenylethanol (prepared as described inPreparation 16), 2.4 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared asdescribed in Preparation 7), 100 ml of benzene, 100 ml of absolutemethanol and 0.95 g of sodium cyanoborohydride were used and that, afterthe reaction, the reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was then concentrated by evaporationunder reduced pressure, and the concentrate was purified by columnchromatography through silica gel, using a 30:1 by volume mixture ofethyl acetate and ethanol as the eluent. 0.53 g of the title compoundwas obtained as crystals, melting at 93°-96° C. (after recrystallizationfrom ethyl acetate).

EXAMPLE 202-[2-(3-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol1/4 hydrate (Compound No. 3-2)

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 3.11 g of methyl 3-(2-oxopropoxy)phenylacetate (preparedas described in Preparation 17), 70 ml of benzene, 60 ml of absolutemethanol and 2.45 g of sodium cyanoborohydride, 2.57 g of the titlecompound were obtained having an Rf=0.38 (thin layer chromatography oversilica gel, using ethyl acetate as the developing solvent).

EXAMPLE 212-[2-(2-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(Compound No. 3-3)

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 3.11 g of methyl 2-(2-oxopropoxy)phenylacetate (preparedas described in Preparation 18), 70 ml of benzene, 60 ml of absolutemethanol and 2.5 g of sodium cyanoborohydride, 3.1 g of the titlecompound were obtained having an Rf=0.30 (thin layer chromatography oversilica gel, using ethyl acetate as the developing solvent).

EXAMPLE 222-[2-(4-Methoxycarbonylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(Compound No. 3-28)

Following a procedure similar to that described in Example 6, but using5.15 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 10.3 g of methyl 3-chloro-4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 19), 200 ml of benzene, 100 ml ofabsolute methanol and 6 g of sodium cyanoborohydride, 1.2 g of the titlecompound were obtained as crystals, melting at 83°-103° C. (afterrecrystallization from a mixture of ethyl acetate and hexane).

EXAMPLE 232-[2-(4-Carbamoylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol1/8 hydrate (Compound No. 4-6)

A solution of 2 g of 2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol (prepared as described inExample 22) dissolved in 50 ml of methanol was saturated with gaseousammonia in a reaction vessel, whilst ice-cooling, after which thereaction vessel was tightly stoppered and allowed to stand at roomtemperature for one week. At the end of this time, the solvent(methanol) was removed by distillation under reduced pressure, and theresidue was recrystallized from ethyl acetate, to give 0.55 g of thetitle compound as crystals, melting at 99°-101° C.

EXAMPLE 242-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanolfumarate (fumarate of Compound No. 3-1)

A mixture of 10.0 g of2-[2-(4-methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(prepared as described in Example 3) and 2.8 g of fumaric acid wasdissolved in methanol and then the methanol was removed by distillationunder reduced pressure. The residue was recrystallized from ethylacetate, to give 11.5 g of the title compound as crystals, melting at130°-146° C.

EXAMPLE 252-{2-[3,4-Bis(hydroxymethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 7-7)

Following a procedure similar to that described in Example 1, but using2.53 g of2-{2-[3,4-bis(methoxycarbonyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(prepared as described in Preparation 20), 0.91 g of lithium aluminumhydride and 100 ml of dry tetrahydrofuran, and then purifying thereaction product by column chromatography through silica gel, using a5:1 by volume mixture of ethyl acetate and ethanol as the eluent, 1.04 gof the title compound were obtained having an Rf=0.37 (thin layerchromatography over silica gel, using a 5:1 by volume mixture of ethylacetate and ethanol as the developing solvent).

EXAMPLE 262-{2-[4-(1,1,2,2-Tetrakis(ethoxycarbonyl)ethyl-phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 3-22)

Following a procedure similar to that described in Example 6, but using1 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 3 g of4-[1,1,2,2-tetrakis(ethoxycarbonyl)ethyl]phenoxyacetone (prepared asdescribed in Preparation 22), 100 ml of dry benzene, 50 ml of absolutemethanol and 920 mg of sodium cyanoborohydride, and then purifying thereaction product by column chromatography through silica gel, using a10:1 by volume mixture of ethyl acetate and hexane as the eluent, 0.4 gof the title compound was obtained having an Rf=0.35 (thin layerchromatography over silica gel, using ethyl acetate as the developingsolvent).

EXAMPLE 272-[2-(4-Methoxycarbonylmethylphenoxy)-1(R)-methylethyl]amino-1 (R)-phenylethanol (Compound No. 3-29)

870 mg of tetrabutylammonium fluoride were added to a solution of 510 mgofN-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-phenylethanamine(prepared as described in Preparation 29) in 15 ml of tetrahydrofuran,and the resulting mixture was stirred at room temperature for 2 hours.At the end of this time, the reaction mixture was diluted with water,and the aqueous mixture was extracted with ethyl acetate. The extractwas dried over anhydrous sodium sulfate, and then the solvent wasremoved by distillation under reduced pressure. The resulting residuewas purified by column chromatography through silica gel, using ethylacetate as the eluent, to give 0.23 g of the title compound as crystals,melting at 69°-70° C.

[α]_(D) ²³ -20.0° (c=1.000 chloroform).

EXAMPLE 282-[2-(4-Methoxycarbonylmethylphenoxy)-1(S)-methylethyl]amino-1(S)-phenylethanol(Compound No. 3-29)

Following a procedure similar to that described in Example 27, but using970 mg ofN-[2-(4-methoxycarbonylmethylphenoxy)-1(S)-methylethyl]-2(S)-t-butyldimethylsilyloxy-2-phenylethanamine(prepared as described in Preparation 30), 20 ml of tetrahydrofuran and1.7 g of tetrabutylammonium fluoride, 0.58 g of the title compound wasobtained as crystals, melting at 70°-71° C.

[α]_(D) ²³ +21.2° (c=1.02 chloroform).

EXAMPLE 292-[2-(4-Methoxycarbonylmethylphenoxy)-1(S)-methylethyl]amino-1(R)-phenylethanol(Compound No. 3-29)

Following a procedure similar to that described in Example 27, but using460 mg ofN-[2-(4-methoxycarbonylmethylphenoxy)-1(S)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-phenylethanamine(prepared as described in Preparation 31), 15 ml of tetrahydrofuran and780 mg of tetrabutylammonium fluoride, 0.23 g of the title compound wasobtained as crystals, melting at 89°-90° C.

[α]_(D) ²³ -44.9° (c=1.002, chloroform).

EXAMPLE 302-[2-(4-Methoxycarbonylmethylphenoxy)-1(R)-methylethyl]amino-1(S)-phenylethanol(Compound No. 3-29)

Following a procedure similar to that described in Example 27, but using880 mg ofN-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(S)-t-butyldimethylsilyloxy-2-phenylethanamine(prepared as described in Preparation 32), 20 ml of tetrahydrofuran and1.5 g of tetrabutylammonium fluoride, 0.5 g of the title compound wasobtained as crystals, melting at 90°-91° C.

[α]_(D) ²³ +45.2° (c=1.000, chloroform).

EXAMPLE 312-[2-(3-Methoxycarbonylmethyl-4-hydroxyphenoxy)-1-methylethyl]amino-1-phenylethanol1/4 hydrate (Compound No. 3-60)

Following a procedure similar to that described in Example 6, but using0.72 g of 2-amino-1-phenylethanol, 1.5 g of methyl2-hydroxy-5-(2-oxopropoxy)phenylacetate (prepared as described inPreparation 21), 60 ml of benzene, 50 ml of absolute methanol and 1.9 gof sodium cyanoborohydride, and then purifying the reaction product bycolumn chromatography through silica gel, using a 10:1 by volume mixtureof ethyl acetate and ethanol as the eluent, 0.07 g of the title compoundwas obtained having an Rf=0.40 (thin layer chromatography over silicagel, using a 10:1 by volume mixture of ethyl acetate and ethanol as thedeveloping solvent).

EXAMPLE 322-{2-[2,4-Bis(hydroxymethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol1/4 hydrate (Compound No. 7-8)

Following a procedure similar to that described in Example 1, but using1.28 g of2-{2-[2,4-bis(methoxycarbonyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(prepared as described in Preparation 33), 0.463 g of lithium aluminumhydride and 70 ml of dry tetrahydrofuran, and then purifying thereaction product by column chromatography through silica gel, using a4:1 by volume mixture of ethyl acetate and ethanol as the eluent, 0.78 gof the title compound was obtained having an Rf=0.34 (thin layerchromatography over silica gel, using a 4:1 by volume mixture of ethylacetate and ethanol as the developing solvent).

EXAMPLE 332-[2-(4-Methoxycarbonylmethyl-2-hydroxyphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(Compound No. 3-23)

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 3.07 g of methyl 3-hydroxy-4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 34), 70 ml of dry benzene, 60 mlof absolute methanol and 1.7 g of sodium cyanoborohydride, and thenpurifying the reaction product by column chromatography through silicagel, using ethyl acetate as the eluent, 2.62 g of the title compoundwere obtained as crystals, melting at 68° C.

EXAMPLE 342-{2-[2-Chloro-4-(N-hydroxycarbamoylmethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 4-15)

A mixture comprising 2.0 g of2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(prepared as described in Example 22), 6.25 g of hydroxylaminehydrochloride, 50 ml of methanol and 11 g of triethylamine was allowedto stand at room temperature for 8 days and then the solvent (methanol)was removed by distillation under reduced pressure. The resultingresidue was mixed with ethyl acetate and with an aqueous solution ofsodium chloride. The ethyl acetate layer was then separated and washedwith an aqueous solution of sodium chloride; it was then dried overanhydrous sodium sulfate. The solvent was removed by distillation underreduced pressure, and the resulting residue was purified by columnchromatography through silica gel, using a 5:2 by volume mixture ofethyl acetate and ethanol as the eluent, to give 1.1 g of the titlecompound as a glassy solid, melting at 65°-75° C.

EXAMPLE 352-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol1/2 fumarate (1/2 fumarate of Compound No. 3-27)

A procedure similar to that described in Example 6 was repeated, exceptthat 3 g of 2-amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol (preparedas described in Preparation 35), 2.2 g of methyl4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3),100 ml of benzene, 60 ml of absolute methanol and 4 g of sodiumcyanoborohydride were used, and that the product was purified byrepeated column chromatography through silica gel, using as the eluentfirst ethyl acetate and then a 1:1 by volume mixture of benzene andethyl acetate. 2.1 g of2-[2-(4-methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanolwere obtained. This product was then mixed with 246 mg of fumaric acid,and the mixture was recrystallized from ethyl acetate, to give 1.5 g ofthe title compound as crystals, melting at 171°-174° C.

EXAMPLE 362-[2-(4-Carboxymethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol1/4 hydrate (Compound No. 2-12)

A solution of 6.0 g of potassium hydroxide in 10 ml of water was addedto a solution of 2.3 g of2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol(prepared as described in Example 22) in 90 ml of methanol, and theresulting mixture was allowed to stand overnight. At the end of thistime, the reaction mixture was poured into ice-water and the pH of themixture was adjusted to a value of 7 by the addition of 1N aqueoushydrochloric acid, after which it was irradiated with ultrasonic waves.The crystals which precipitated were collected by filtration andrecrystallized from methanol, to give 0.97 g of the title compound ascrystals, melting at 188°-192° C.

EXAMPLE 372-{2-[4-(α-Methoxycarbonyl-α-hydroxymethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 6-1)

Following a procedure similar to that described in Example 6, but using5.2 g of methyl 4-(2-oxopropoxy)mandelate (prepared as described inPreparation 36), 3.12 g of 2-amino-1-(3-chlorophenyl)ethanol (preparedas described in Preparation 8), 80 ml of dry benzene, 80 ml of absolutemethanol and 4.2 g of sodium cyanoborohydride, and then purifying thereaction product by column chromatography through silica gel, usingethyl acetate as the eluent, 3.87 g of the title compound were obtainedhaving an Rf=0.27 (thin layer chromatography over silica gel, usingethyl acetate as the developing solvent).

EXAMPLE 382-{2-[4-(2-Acetoxyethyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 8-1)

Following a procedure similar to that described in Example 6, but using2 g of 2-[4-(2-oxopropoxy)phenyl]ethyl acetate (prepared as described inPreparation 37), 1.45 g of 2-amino-1-(3-chlorophenyl)ethanol (preparedas described in Preparation 8), 60 ml of dry benzene, 50 ml of absoluteisopropanol and 2.06 g of sodium cyanoborohydride, and then purifyingthe reaction product by column chromatography through silica gel, usinga 1:1 by volume mixture of ethyl acetate and hexane as the eluent, 0.49g of the title compound was obtained, having an Rf=0.34 (thin layerchromatography over silica gel, using a 1:1 by volume mixture of ethylacetate and hexane as the developing solvent).

EXAMPLE 392-{2-[4-Bis(methoxycarbonyl)methylphenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol(Compound No. 3-18)

Following a procedure similar to that described in Example 6, but using0.42 g of dimethyl 4-(2-oxopropoxy)phenylmalonate (prepared as describedin Preparation 38), 0.26 g of 2-amino-1-(3-chlorophenyl)ethanol(prepared as described in Preparation 8), 50 ml of dry benzene, 50 ml ofabsolute methanol and 0.9 g of sodium cyanoborohydride, and thenpurifying the reaction product by column chromatography through silicagel, using ethyl acetate as the eluent, 0.4 g of the title compound wasobtained, having an Rf=0.28 (thin layer chromatography over silica gel,using ethyl acetate as the developing solvent).

EXAMPLE 402-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]amino-1-(3,5-dichlorophenyl)ethanol(Compound No. 3-15)

Following a procedure similar to that described in Example 3, but using3.0 g of 2-amino-1-(3,5-dichlorophenyl)ethanol (prepared as described inPreparation 39), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 3), 80 ml of benzene, 60 ml ofabsolute methanol and 2.9 g of sodium cyanoborohydride, and thenpurifying the reaction product by column chromatography through silicagel, using ethyl acetate as the eluent, 3.6 g of the title compound wereobtained, having an Rf=0.51 (thin layer chromatography over silica gel,using ethyl acetate as the developing solvent).

EXAMPLE 412-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]-amino-1-(3-chloro-4-fluorophenyl)ethanol (Compound No. 3-41)

Following a procedure similar to that described in Example 3, but using3.0 g of 2-amino-1-(3-chloro-4-fluorophenyl)ethanol (prepared asdescribed in Preparation 40), 4.22 g of methyl4-(2-oxopropoxy)-phenylacetate (prepared as described in Preparation 3),80 ml of benzene, 60 ml of absolute methanol and 3.5 g of sodiumcyanoborohydride, and then purifying the reaction product by columnchromatography through silica gel, using ethyl acetate as the eluent,3.31 g of the title compound were obtained having an Rf=0.22 (thin layerchromatography over silica gel, using ethyl acetate as the developingsolvent).

EXAMPLE 422-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]-amino-1-(3-bromophenyl)ethanol(Compound No. 3-14)

Following a procedure similar to that described in Example 3, but using3.0 g of 2-amino-1-(3-bromophenyl)-ethanol (prepared as described inPreparation 41), 3.67 g of methyl 4-(2-oxopropoxy)phenylacetate(prepared as described in Preparation 3), 80 ml of benzene, 60 ml ofabsolute methanol and 3.1 g of sodium cyanoborohydride, and thenpurifying the reaction product by column chromatography through silicagel, using ethyl acetate as the eluent, 3.33 g of the title compoundwere obtained having an Rf=0.25 (thin layer chromatography over silicagel, using ethyl acetate as the developing solvent).

EXAMPLE 432-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]-amino-1-(3-trifluoromethylphenyl)ethanol(Compound No. 3-66)

Following a procedure similar to that described in Example 3, but using3.0 g of 2-amino-1-(3-trifluoromethylphenyl)ethanol (prepared asdescribed in Preparation 42), 3.89 g of methyl4-(2-oxopropoxy)-phenylacetate (prepared as described in Preparation 3),80 ml of benzene, 60 ml of absolute methanol and 4.0 g of sodiumcyanoborohydride, and then purifying the reaction product by columnchromatography through silica gel, using ethyl acetate as the eluent,2.2 g of the title compound were obtained having an Rf=0.32 (thin layerchromatography over silica gel, using ethyl acetate as the developingsolvent).

EXAMPLE 44 2-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]-amino-1-(3 -methoxyphenyl)ethanol (Compound No. 3-62)

Following a procedure similar to that described in Example 3, but using2.5 g of 2-amino-1-(3-methoxyphenyl)ethanol (prepared as described inPreparation 43), 4.0 g of methyl 4-(2-oxopropoxy)phenylacetate (preparedas described in Preparation 3), 80 ml of benzene, 60 ml of absolutemethanol and 2.75 g of sodium cyanoborohydride, and then purifying thereaction product by column chromatography through silica gel, usingethyl acetate as the eluent, 3.11 g of the title compound were obtainedhaving an Rf=0.21 (thin layer chromatography over silica gel, usingethyl acetate as the developing solvent).

EXAMPLE 452-[2-(4-Methoxycarbonylmethylphenoxy)-1-methylethyl]-1-(3-methylphenyl)ethanol(Compound No. 3-61)

Following a procedure similar to that described in Example 3, but using2.5 g of 2-amino-1-(3-methylphenyl)ethanol (prepared as described inPreparation 44), 4.4 g of methyl 4-(2-oxopropoxy)phenylacetate (preparedas described in Preparation 3), 80 ml of benzene, 60 ml of absolutemethanol and 4.5 g of sodium cyanoborohydride, and then purifying thereaction product by column chromatography through silica gel, usingethyl acetate as the eluent, 3.2 g of the title compound were obtainedhaving an Rf=0.24 (thin layer chromatography over silica gel, usingethyl acetate as the developing solvent).

EXAMPLE 462-[2-(4-Methoxycarbonylmethylphenoxy)-1(R)-methylethyl]amino-1(R) - (3-chlorophenyl)ethanol (Compound No. 3-1)

Following a procedure similar to that described in Example 27, but using3.02 g of N-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethanamine(prepared as described in Preparation 50), 4.81 g of tetrabutylammoniumfluoride and 100 ml of tetrahydrofuran, 1.7 g of the title compound wereobtained having an Rf=0.39 (thin layer chromatography over silica gel,using ethyl acetate as the developing solvent).

[α]_(D) ²³ -13.2° (c=0.99, methanol).

EXAMPLE 47 2-[2-(4-Methoxycarbonylmethylphenoxy)-1(R)-methylethyl]amino-1(R)-(3-chlorophenyl)ethanolfumarate (fumarate of Compound No. 3-1)

30 ml of hexane were slowly added to a solution of 1.6 g of2-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]amino-1(R)-(3-chlorophenyl)ethanol(prepared as described in Example 46) and 491 mg of fumaric acid in 5 mlof ethyl acetate, whilst irradiating the reaction mixture withultrasonic waves. The crystals which precipitated were collected byfiltration and dried, to give 1.95 g of the title compound as crystals,melting at 73°-78° C.

[α]_(D) ²³ -19.4° (c=1.01, methanol).

EXAMPLE 48 5-[4-{2(R)-[2(R)-(3-Chlorophenyl)-2-hydroxyethyl-amino]propoxy}benzyl]thiazolidine-2,4-dione(Compound No. 5-1)

88 g of tetrabutylammonium fluoride were added, whilst ice-cooling, to asolution of 46.2 g of5-[4-{2(R)-[2(R)-(3-chlorophenyl)-2-t-butyldimethylsilyloxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione(prepared as described in Preparation 52) in 500 ml of tetrahydrofuran,and the resulting mixture was stirred at room temperature for 15 hours.At the end of this time, the tetrahydrofuran solvent was removed bydistillation under reduced pressure, and the residue was mixed withwater and then extracted with ethyl acetate. The extract was washed withan aqueous solution of sodium chloride and then dried over anhydroussodium sulfate. The ethyl acetate solvent was removed by distillationunder reduced pressure, and the residue was purified by columnchromatography through silica gel, using a 5:1 by volume mixture ofethyl acetate and ethanol as the eluent. The crude crystals thusobtained were recrystallized from a mixture of ethyl acetate andethanol, to give 27.1 g of the title compound as crystals, melting at100°-112° C.

[α]_(D) ²³ -4.4° (c=1.005, methanol).

EXAMPLE 49 5-[4-{2-[2-(2-Naphthyl)-2-hydroxyethylamino]-propoxy}benzyl]thiazolidine -2,4- dione(Compound No. 5-2)

Following a procedure similar to that described in Example 2, but using520 mg of 2-amino-1-(2-naphthyl)ethanol (prepared as described inPreparation 9), 650 mg of5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione (prepared as describedin Preparation 2), 150 ml of benzene, 100 ml of absolute methanol and1.25 g of sodium borohydride, and then purifying the reaction product bycolumn chromatography through silica gel, using a 5:1 by volume mixtureof ethyl acetate and ethanol as the eluent, 0.49 g of the title compoundwas obtained as crystals, melting at 115°-145° C.

EXAMPLE 505-[4-{2-[2-(3-Trifluoromethylphenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione(Compound No. 5-3)

Following a procedure similar to that described in Example 2, but using5.88 g of 2-amino-1-(3-trifluoromethylphenyl)ethanol (prepared asdescribed in Preparation 42), 8 g of5-[4-(2-oxopropoxy)benzyl]-thiazolidine-2,4-dione (prepared as describedin Preparation 2), 200 ml of benzene, 150 ml of absolute methanol and5.4 g of sodium cyanoborohydride, and then purifying the reactionproduct by column chromatography through silica gel, using ethyl acetateas the eluent, 4.8 g of the title compound were obtained as crystals,melting at 100°-105° C.

PREPARATION 12-[2-(4-Methoxycarbonylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol

A procedure similar to that described in Example 12 was repeated, exceptthat 3.43 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as describedin Preparation 8), 4.5 g of methyl 4-(2-oxopropoxy)benzoate (prepared asdescribed in European Patent Publication No. 6735), 100 ml of benzene,100 ml of absolute methanol and 2.7 g of sodium borohydride were used,to give the title compound as crystals, melting at 99°-101° C.

PREPARATION 2 5-[4-(2-Oxopropoxy)benzyl]thiazolidine-2,4-dione

2(a) 1-(4-Aminophenoxy)propan-2-one hydrochloride

A stream of hydrogen was passed through a mixture comprising 19.6 g of1-(4-nitrophenoxy)propan-2-one, 300 ml of methanol, 30 ml ofconcentrated aqueous hydrochloric acid and 4 g of 10% w/vpalladium-on-charcoal at room temperature for 5 hours. At the end ofthis time, the catalyst was filtered off, and the filtrate wasconcentrated by evaporation under reduced pressure, to give 20 g of thetitle compound.

2(b) Ethyl 2-chloro-3-[4-(2-oxopropoxy)phenyl]propionate

50 ml of 35% w/v aqueous hydrochloric acid were added to a mixture of 20g of the 1-(4-aminophenoxy)-propan-2-one hydrochloride [prepared asdescribed in step (a) above] and 400 ml of acetone, and then a solutionof 12 g of sodium nitrite in 20 ml of water was added dropwise to theresulting mixture, whilst ice-cooling; the mixture was then stirred atthe same temperature for 20 minutes. At the end of this time, 130 g ofethyl acrylate and then 3.2 g of cuprous oxide were added in portions tothe mixture, and the resulting mixture was stirred at room temperaturefor 1 hour. The reaction mixture was then concentrated by evaporationunder reduced pressure, and the concentrate was mixed with water andethyl acetate. The ethyl acetate layer was separated, washed with waterand dried over anhydrous sodium sulfate; the solvent was then removed bydistillation under reduced pressure. The resulting residue was purifiedby column chromatography through silica gel, using a 5:1 by volumemixture of hexane and ethyl acetate as the eluent, to give 11.3 g of thetitle compound having an Rf=0.31 (thin layer chromatography over silicagel, using a 5:1 by volume mixture of hexane and ethyl acetate as thedeveloping solvent).

2(c) 5-[4-(2-Oxopropoxy)benzyl]thiazolidine-2,4-dione

A mixture comprising 12 g of ethyl2-chloro-3-[4-(2-oxopropoxy)phenyl]propionate [prepared as described instep (b) above], 5 g of thiourea and 30 ml of sulfolane was heated at90° C. for 3 hours, and then 100 ml of methoxyethanol were added to themixture, which was then heated for a further 4 hours. At the end of thistime, 40 ml of water and 20 ml of concentrated aqueous hydrochloric acidwere added to the reaction mixture, and the resulting mixture was heatedfor 4.5 hours in an oil bath kept at 100° C. After this, the reactionmixture was mixed with water and ethyl acetate, and then the ethylacetate layer was separated, washed with water and dried over anhydroussodium sulfate; the solvent was then removed by distillation underreduced pressure. The resulting residue was purified by columnchromatography through silica gel, using a gradient elution method, withmixtures of hexane and ethyl acetate ranging from 3:2 to 2:3 by volumeas the eluent, followed by crystallization from a mixture of ethylacetate and hexane, to give the title compound as crystals, melting at158°-159° C.

PREPARATION 3 Methyl 4-(2-oxopropoxy)phenylacetate

A mixture comprising 74.6 g of methyl 4-hydroxyphenylacetate, 92.2 g ofbromoacetone, 125 g of potassium carbonate and 750 ml ofdimethylformamide was stirred at room temperature for 1 day. At the endof this time, the reaction mixture was concentrated by evaporation underreduced pressure. The resulting concentrate was mixed with water andthen extracted with ethyl acetate. The extract was washed with anaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate; the solvent was then removed by distillation under reducedpressure. The residue was purified by column chromatography throughsilica gel, using a 1:8 by volume mixture of ethyl acetate and benzeneas the eluent, to give the title compound having an Rf=0.43 (thin layerchromatography over silica gel, using a 1:7 by volume mixture of ethylacetate and benzene as the developing solvent).

PREPARATION 4 Methyl 4-(2-oxopropoxy)cinnamate

Following a procedure similar to that described in Preparation 3, butusing 16 g of methyl 4-hydroxycinnamate, 14.9 g of bromoacetone, 20 g ofpotassium carbonate and 150 ml of dimethylformamide, the title compoundwas obtained as crystals, melting at 117°-118° C. (afterrecrystallization from ethyl acetate).

PREPARATION 5

Methyl 3-[4-(2-oxopropoxy) phenyl]propionate

A stream of hydrogen was passed through a solution of 4 g of methyl4-(2-oxopropoxy) cinnamate (prepared as described in Preparation 4) in amixture of 200 ml of methanol and 100 ml of tetrahydrofuran and in thepresence of 2 g of 10% w/w palladium-on-charcoal at room temperature for2 hours. At the end of this time, the catalyst was filtered off, and thefiltrate was concentrated by evaporation under reduced pressure. Theresulting concentrate was purified by column chromatography throughsilica gel, using ethyl acetate as the eluent, to give the titlecompound having an Rf=0.54 (thin layer chromatography over Silica gel,using a 2:1 by volume mixture of hexane and ethyl acetate as thedeveloping solvent).

PREPARATION 6

Methyl 3-[4-(2-oxopropoxy)phenyl]lactate

Following a procedure similar to that described in Preparation 3, butusing 1.8 g of methyl 4-hydroxyphenyllactate, 1.63 g of bromoacetone,1.65 g of potassium carbonate and 150 ml of dimethylformamide, the titlecompound was obtained having an Rf=0.32 (thin layer chromatography oversilica gel, using a 1:1 by volume mixture of hexane and ethyl acetate asthe developing solvent).

PREPARATION 7 2-[4-(2 -Oxopropoxy)phenyl]ethanol

Following a procedure similar to that described in Preparation 3, butusing 10 g of 2-(4-hydroxyphenyl)-ethanol, 21.6 g of bromoacetone, 30 gof potassium carbonate and 100 ml of dimethylformamide, the titlecompound was obtained having an Rf=0.31 (thin layer chromatography oversilica gel, using a 1:1 by volume mixture of hexane and ethyl acetate asthe developing solvent).

PREPARATION 8

2 -Amino-1-(3-chlorophenyl)ethanol

140 g of 3-chlorobenzaldehyde were added dropwise to a mixture of 112 gof trimethylsilylnitrile and 0.1 g of zinc iodide, and the resultingmixture was heated in an oil bath kept at 90° C. for 2.5 hours. At theend of this time, the reaction mixture was added dropwise to a mixtureof 50 g of lithium aluminum hydride and 1200 ml of tetrahydrofuran, andthe mixture was then heated under reflux for 40 minutes. It was thencooled with ice, after which 50 ml of water, 50 ml of a 15% w/v aqueoussolution of sodium hydroxide and 50 ml of water were added, in thatorder. Insoluble materials were filtered off, and the filtrate wasconcentrated by evaporation under reduced pressure. The concentrate waspurified by column chromatography through silica gel, using a 10:4:1 byvolume mixture of ethyl acetate, ethanol and triethylamine as theeluent, followed by distillation in vacuo, to give the title compound asa liquid boiling at 140°-141° C./2.5 mmHg (333 Pa).

PREPARATION 9 2 -Amino -1-(2-naphthyl)ethanol

A mixture of 7.4 g of 2-naphthaldehyde, 9.93 g of trimethylsilylnitrileand a catalytic amount of zinc iodide was heated in an oil bath kept at90° C. for 2 hours. At the end of this time, the reaction mixture wasadded dropwise to a mixture of 5.7 g of lithium aluminum hydride and 500ml of tetrahydrofuran, whilst ice-cooling, and the resulting mixture wasthen heated under reflux for 3 hours, after which 5.7 ml of water, 5.7ml of a 15% w/v aqueous solution of sodium hydroxide and 17.1 ml ofwater were added dropwise, in that order. Insoluble materials werefiltered off and the filtrate was concentrated by evaporation underreduced pressure. The crystals obtained from the concentrate wererecrystallized from a mixture of ethyl acetate and hexane, to give thetitle compound as crystals, melting at 113°-116° C.

PREPARATION 10

2 -Amino -1-(1-naphthyl)ethanol

Following a procedure similar to that described in Preparation 9, butusing 7.4 g of 1-naphthaldehyde, 9.93 g of trimethylsilylnitrile, acatalytic amount of zinc iodide and 500 ml of tetrahydrofuran, the titlecompound was obtained as crystals, melting at 124°-126.5° C.

PREPARATION 11 2-Amino-1-(2-chlorophenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 6.75 g of 2-chlorobenzaldehyde, 9.93 g of trimethylsilylnitrile, acatalytic amount of zinc iodide, 5.7 g of lithium aluminum hydride and500 ml of tetrahydrofuran, the title compound was obtained as a liquid,boiling at 132° C./2 mmHg (266 Pa).

PREPARATION 12 2 -Amino-1-(4-chlorophenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 6.75 g of 4-chlorobenzaldehyde, 9.93 g of trimethylsilylnitrile, acatalytic amount of zinc iodide, 5.7 g of lithium aluminum hydride and500 ml of tetrahydrofuran, the title compound was obtained as a liquid,boiling at 141° C./2 mmHg (266 Pa).

PREPARATION 13 2-Amino-1-(3-fluorophenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 6 g of 3-fluorobenzaldehyde, 12.5 ml of trimethylsilylnitrile, acatalytic amount of zinc iodide, 5.7 g of lithium aluminum hydride and500 ml of tetrahydrofuran, the title compound was obtained as a liquid,boiling at 117° C./1.5 mmHg (200 Pa).

PREPARATION 14 2 -Amino-1-(3,4,5-trimethoxyphenyl)ethanol

Following a procedure similar to that described in Preparation 9, butusing 9.42 g of 3,4,5-trimethoxybenzaldehyde, 12.5 ml oftrimethylsilylnitrile, a catalytic amount of zinc iodide, 5.7 g oflithium aluminum hydride and 500 ml of tetrahydrofuran, the titlecompound was obtained as crystals, melting at 141° C. (afterrecrystallization from ethyl acetate).

PREPARATION 15 2-Amino-1-(3-phenoxyphenyl)ethanol

10 g of 3-phenoxybenzaldehyde cyanohydrin were added dropwise to amixture of 5.1 g of lithium aluminum hydride and 500 ml oftetrahydrofuran, whilst ice-cooling, and the resulting mixture washeated under reflux for 4 hours. At the end of this time, 5 ml of water,6 ml of a 15% w/v aqueous solution of sodium hydroxide and 18 ml ofwater were added in that order to the reaction mixture, whilstice-cooling. Insoluble materials were filtered off, and the filtrate wasconcentrated by evaporation under reduced pressure. The concentrate waspurified by column chromatography through silica gel, using a 3:1 byvolume mixture of ethyl acetate and ethanol as the eluent, to give thetitle compound having an Rf=0.32 (thin layer chromatography over silicagel, using a 5:5:1 by volume mixture of ethyl acetate, ethanol andtriethylamine as the developing solvent).

PREPARATION 16 2-Amino-1(S)-phenylethanol

16(a) Ethyl (S)-α-t-butyldimethylsilyoxy-α-phenylacetate

A solution of 31.4 g of t-butyldimethylsilyl chloride in 200 ml ofdimethylformamide was added dropwise to a solution of 25 g of ethyl(S)-(+)-mandelate and 28.4 g of imidazole in 800 ml ofdimethylformamide, and the resulting mixture was stirred overnight at40° C. At the end of this time, the dimethylformamide solvent wasremoved by distillation under reduced pressure, and the resultingresidue was purified by column chromatography through silica gel, usinga 10:1 by volume mixture of hexane and ethyl acetate as the eluent, togive the title compound having an Rf=0.84 (thin layer chromatographyover silica gel, using a 10:1 by volume mixture of hexane and ethylacetate as the developing solvent).

16(b) 2(S) -t-Butyldimethylsilyoxy-2-phenylethanol

15.5 g of sodium borohydride were added in portions, whilst ice-cooling,to a solution of 20 g of ethyl(S)-α-t-butyldimethylsilyloxy-α-phenylacetate [prepared as described instep (a) above] in 500 ml of absolute methanol, and the resultingmixture was stirred overnight at room temperature. At the end of thistime, 10 g of sodium borohydride were added in portions, whilstice-cooling. The reaction mixture was then stirred at room temperaturefor 5 hours, after which it was concentrated by evaporation underreduced pressure, and the concentrate was mixed with water and ethylacetate. The ethyl acetate layer was separated, washed with water anddried over anhydrous sodium sulfate, and then the solvent was removed bydistillation under reduced pressure, to give the title compound as acrude product.

16(c) 2(S)-t-Butyldimethylsilyloxy-2-phenylethylazide

A solution of 13.36 g of crude2(S)-t-butyl-dimethylsilyloxy-2-phenylethanol [prepared as described instep (b) above] and 5.36 g of triethylamine in 450 ml of tetrahydrofuranwas cooled in an ice-acetone bath. A solution of 6.68 g ofmethanesulfonyl chloride in 50 ml of tetrahydrofuran was added dropwiseto the solution, and the resulting mixture was stirred for 1 hour,whilst ice-cooling. The tetrahydrofuran solvent was then removed bydistillation under reduced pressure, and the residue was mixed withwater, with ethyl acetate and with an aqueous solution of sodiumchloride. The ethyl acetate layer was separated, washed with an aqueoussolution of sodium chloride and dried over anhydrous sodium sulfate; thesolvent was then removed by distillation under reduced pressure. Theresulting residue was dissolved in 300 ml of dimethylformamide, and10.48 g of sodium azide were added to the solution thus obtained, whichwas then stirred overnight at 80° C. At the end of this time, thereaction mixture was freed from the dimethylformamide solvent bydistillation under reduced pressure. The resulting residue was mixedwith ethyl acetate and with an aqueous solution of sodium chloride. Theethyl acetate layer was separated, washed with an aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. The ethylacetate solvent was then removed by distillation under reduced pressure,and the resulting residue was purified by column chromatography throughsilica gel, using a 1:50 by volume mixture of ethyl acetate and hexaneas the eluent, to give the title compound.

16(d) 2-Amino-1(S)-phenylethanol

A mixture of 2.6 g of lithium aluminum hydride in 400 ml oftetrahydrofuran was cooled in an ice-acetone bath, and a solution of 9.4g of 2(S)-t-butyldimethyl-silyloxy-2-phenylethylazide [prepared asdescribed in step (c) above] in 100 ml of tetrahydrofuran was addeddropwise to the cooled mixture. The mixture was stirred for 1 hour,whilst ice-cooling, after which 2.6 ml of water, 2.6 ml of a 15% w/vaqueous solution of sodium hydroxide and 7.8 ml of water were addeddropwise to the reaction mixture, in that order. Insoluble materialswere filtered off, and the filtrate was concentrated by evaporationunder reduced pressure. The resulting residue was purified by columnchromatography through silica gel, using a 1:2 by volume mixture ofethyl acetate and ethanol as the eluent, to give the title compound ascrystals, melting at 69°-70° C.

PREPARATION 17 Methyl 3-(2-oxopropoxy)phenylacetate

Following a procedure similar to that described in Preparation 3, butusing 2.8 g of methyl 3-hydroxyphenylacetate, 3.5 g of bromoacetone, 4 gof potassium carbonate and 30 ml of dimethylformamide, the titlecompound was obtained having an Rf=0.41 (thin layer chromatography oversilica gel, using a 2:5 by volume mixture of ethyl acetate and hexane asthe developing solvent).

PREPARATION 18

Methyl 2-(2-oxopropoxy)phenylacetate

Following a procedure similar to that described in Preparation 3, butusing 15.6 g of methyl 2-hydroxyphenylacetate, 34 g of bromoacetone, 25g of potassium carbonate and 170 ml of dimethylformamide, the titlecompound was obtained having an Rf=0.39 (thin layer chromatography oversilica gel, using a 3:1 by volume mixture of hexane and ethyl acetate asthe developing solvent).

PREPARATION 19

Methyl 3-chloro-4-(2-oxopropoxy)phenylacetate

Following a procedure similar to that described in Preparation 3, butusing 20 g of methyl 3-chloro-4-hydroxyphenylacetate, 27 g ofbromoacetone, 28 g of potassium carbonate and 300 ml ofdimethylformamide, the title compound was obtained having an Rf=0.33(thin layer chromatography over silica gel, using a 3:1 by volumemixture of hexane and ethyl acetate as the developing solvent).

PREPARATION 202-{2-[3,4-Bis(methoxycarbonyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol

Following a procedure similar to that described in Example 6, but using2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 3.73 g of dimethyl 4-(2-oxopropoxy)phthalate (preparedas described in Preparation 54), 70 ml of benzene, 60 ml of absolutemethanol and 1.32 g of sodium borohydride, the title compound wasobtained having an Rf=0.29 (thin layer chromatography over silica gel,using ethyl acetate as the developing solvent).

PREPARATION 21 Methyl 2-hydroxy-5-(2-oxopropoxy)phenylacetate

A mixture of 5 g of 2,5-dihydroxyphenylacetic acid, 15 ml of absolutemethanol and 15 ml of a 4N solution of hydrogen chloride in dioxane wasallowed to stand overnight, after which the solvent was removed bydistillation under reduced pressure. The residue was dissolved in ethylacetate, and the resulting solution was washed twice with water and thendried over anhydrous sodium sulfate. The ethyl acetate solvent wasremoved by distillation under reduced pressure, after which 4 g of theresidue were mixed with 70 ml of anhydrous dimethylformamide, 3.32 g ofbromoacetone and 3.04 g of potassium carbonate, and the resultingmixture was stirred overnight at room temperature. At the end of thistime, the reaction mixture was poured into water, neutralized withaqueous hydrochloric acid and extracted with ethyl acetate. The extractwas washed with water and dried over anhydrous sodium sulfate. Thesolvent was then removed by distillation under reduced pressure. Theresulting residue was purified by column chromatography through silicagel, using first a 1:2 and subsequently a 3:4 by volume mixture of ethylacetate and hexane as the eluent, to give the title compound having anRf=0.43 (thin layer chromatography over silica gel, using a 1:2 byvolume mixture of ethyl acetate and hexane as the developing solvent).

PREPARATION 22 p -[1,1,2,2-Tetrakis(ethoxycarbonyl)ethyl]phenoxyacetone

Following a procedure similar to that described in Preparation 3, butusing 11.7 g of p-[1,1,2,2-tetrakis(ethoxycarbonyl)ethyl]phenol, 7.9 gof bromoacetone, 7.9 g of potassium carbonate and 100 ml ofdimethylformamide, and then purifying the reaction product by columnchromatography through silica gel, using a 1:2 by volume mixture ofethyl acetate and hexane as the eluent, the title compound was obtainedhaving an Rf=0.21 (thin layer chromatography over silica gel, using a1:2 by volume mixture of ethyl acetate and hexane as the developingsolvent).

PREPARATION 23 Ethyl (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetate

A solution of 31.4 g of t-butyldimethylsilyl chloride in 200 ml ofdimethylformamide was added dropwise to a solution of 25 g of ethyl(R)-(-)-mandelate and 28.4 g of imidazole in 600 ml of anhydrousdimethylformamide, and the resulting mixture was stirred overnight at40° C. The dimethylformamide solvent was then removed by distillationunder reduced pressure, and the residue was mixed with water and thenextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate, and the solvent was then removed by distillation underreduced pressure. The resulting residue was purified by columnchromatography through silica gel, using a 1:10 by volume mixture ofethyl acetate and hexane as the eluent. The title compound was obtainedas a liquid, boiling at 129° C./3.5 mmHg (466 Pa) by distillation invacuo.

[α]_(D) ²³ -40.8° (c=1.07, chloroform).

PREPARATION 24 Ethyl (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetate

Following a procedure similar to that described in Preparation 23, butusing 23.8 g of ethyl (S)-(+)-mandelate, 26.6 g of imidazole, 400 ml ofdimethylformamide, 30.1 g of t-butyldimethylsilyl chloride and 100 ml ofdimethylformamide, the title compound was obtained as a liquid, boilingat 125.5°/3.0 mmHg (400 Pa).

[α]_(D) ²³ +40.9° (c=1.02, chloroform).

PREPARATION 25 (R)-α-(t-Butyldimethylsilyloxy)-α-phenylacetaldehyde

20 ml of a 1M hexane solution of diisobutylaluminum hydride were addeddropwise at -65° C. and in an atmosphere of nitrogen to a solution of5.9 g of ethyl (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetate (preparedas described in Preparation 23) in 300 ml of dry hexane, and theresulting mixture was stirred at -40° C. for 4 hours. At the end of thistime, 10 ml of a tetrahydrofuran solution containing 1 ml of water wasadded dropwise to the reaction mixture at -40° C., and then the mixturewas stirred at room temperature for 1.5 hours. The reaction mixture wasthen filtered using a Celite (trade mark) filter aid, and the filtratewas concentrated by evaporation under reduced pressure. The resultingresidue was purified by column chromatography through silica gel, usinga 1:60 by volume mixture of ethyl acetate and hexane as the eluent, togive the title compound having an Rf=0.64 (thin layer chromatographyover silica gel, using a 1:50 by volume mixture of ethyl acetate andhexane).

PREPARATION 26 (S)-α-(t-Butyldimethylsilyloxy)-α-phenylacetaldehyde

Following a procedure similar to that described in Preparation 25, butusing 8.8 g of ethyl (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetate(prepared as described in Preparation 24), 300 ml of dry hexane and 30ml of a 1M solution of diisobutylaluminum hydride in hexane, and thenpurifying the reaction product by column chromatography through silicagel, using a 1:60 by volume mixture of ethyl acetate and hexane as theeluent, the title compound was obtained having an Rf=0.29 (thin layerchromatography over silica gel, using a 1:80 by volume mixture of ethylacetate and hexane as the developing solvent).

PREPARATION 27 Methyl 4-[2(R)-amino-1-propoxy]phenylacetate

16.6 g of diethyl azodicarboxylate were added, whilst ice-cooling, to asolution of 16.8 g of (R)-2-t-butoxycarbonylamino-1-propanol, 10.0 g ofmethyl 4-hydroxyphenylacetate and 24.0 g of triphenylphosphine in 50 mlof dry benzene, and the resulting mixture was stirred at roomtemperature for 2 days. At the end of this time, the benzene solvent wasremoved by distillation under reduced pressure. The resulting residuewas dissolved in 100 ml of methanol, and 200 ml of a 4N solution ofhydrogen chloride in dioxane were added to the solution thus obtained,whilst ice-cooling, after which the mixture was allowed to stand at roomtemperature for 3 hours. The reaction mixture was then poured intowater, and the pH of the aqueous mixture was adjusted to a value of 8 to9 by the addition of an aqueous solution of potassium carbonate, andthen the mixture was extracted with ethyl acetate. The extract was driedover anhydrous sodium sulfate, and the ethyl acetate solvent was removedby distillation under reduced pressure. The resulting residue waspurified by column chromatography through silica gel, using a 3:1 byvolume mixture of ethyl acetate and ethanol as the eluent, to give thetitle compound.

[α]_(D) ²³ -13.2° (c=1 048, chloroform).

PREPARATION 28 Methyl 4 -[2(S)-amino-1-propoxy]phenylacetate

Following a procedure similar to that described in Preparation 27, butusing 15.8 g of (S)-2-t-butoxycarbonylamino-1-propanol, 10.0 g of methyl4-hydroxyphenylacetate, 24 g of triphenylphosphine, 70 ml of drybenzene, 15.7 g of diethyl azodicarboxylate, 50 ml of methanol and 70 mlof a 4N solution of hydrogen chloride in dioxane, the title compound wasobtained.

[α]_(D) ²³ +12.1° (c=1.054, chloroform).

PREPARATION 29N-[2-(4-Methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-phenylethanamine

630 mg of sodium cyanoborohydride were added, whilst ice-cooling, to asolution of 1.01 g of(R)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared asdescribed in Preparation 25) and 750 mg of methyl4-(2(R)-amino-1-propoxy)phenylacetate (prepared as described inPreparation 27) in 10 ml of absolute methanol, and the resulting mixturewas allowed to stand overnight at room temperature. At the end of thistime, the reaction mixture was mixed with ethyl acetate and water. Theorganic layer was separated, washed with water and dried over anhydroussodium sulfate, after which the solvent was removed by distillationunder reduced pressure. The resulting residue was purified by columnchromatography through silica gel, using a 1:4 by volume mixture ofethyl acetate and hexane as the eluent, to give the title compound.

[α]_(D) ²³ -38.3° (c=1.138, chloroform).

PREPARATION 30N-[2-(4-Methoxycarbonylmethylphenoxy)-1(S)-methylethyl]-2(S)-t-butyldimethylsilyloxy-2-phenylethanamine

Following a procedure similar to that described in Preparation 29, butusing 1.5 g of (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde(prepared as described in Preparation 26), 1.1 g of methyl4-[2(S)-amino-1-propoxy]phenylacetate (prepared as described inPreparation 28), 10 ml of absolute methanol and 950 mg of sodiumcyanoborohydride, the title compound was obtained.

[α]_(D) ²³ +38.3° (c=1.116, chloroform).

PREPARATION 31N-[2-(4-Methoxycarbonylmethylphenoxy)-1(S)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-phenylethanamine

Following a procedure similar to that described in Preparation 29, butusing 750 mg of (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde(prepared as described in Preparation 25), 920 mg of methyl4-[2(S)-amino-1-propoxy]phenylacetate (prepared as described inPreparation 28), 10 ml of absolute methanol and 500 mg of sodiumcyanoborohydride, the title compound was obtained.

[α]_(D) ²³ -58.6° (c=0.998 chloroform).

PREPARATION 32N-[2-(4-Methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(S)-t-butyldimethylsilyloxy-2-phenylethanamine

Following a procedure similar to that described in Preparation 29, butusing 1.5 g of (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde(prepared as described in Preparation 26), 1.1 g of methyl4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described inPreparation 27), 10 ml of absolute methanol and 950 mg of sodiumcyanoborohydride, the title compound was obtained.

[α]_(D) ²³ +58.4° (c=0.998 chloroform).

PREPARATION 332-{2-[2,4-Bis(methoxycarbonyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol

Following a procedure similar to that described in Example 8, but using1.3 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described inPreparation 8), 2.31 g of dimethyl 4-(2-oxopropoxy) isophthalate(prepared as described in Preparation 55), 60 ml of benzene, 50 ml ofabsolute methanol and 0.73 g of sodium borohydride, and then purifyingthe reaction product by column chromatography through silica gel, usinga 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, thetitle compound was obtained as crystals, melting at 112° C.

PREPARATION 34

Methyl 3-hydroxy-4-(2-oxopropoxy)phenylacetate

Following a procedure similar to that described in Preparation 21, butusing 10 g of 3,4-dihydroxyphenylacetic acid, 30 ml of absolutemethanol, 20 ml of a 4N solution of hydrogen chloride in dioxane, 200 mlof anhydrous dimethylformamide, 8.74 g of bromoacetone and 8.02 g ofpotassium carbonate, the title compound was obtained having an Rf=0.37(thin layer chromatography over silica gel, using a 1:2 by volumemixture of ethyl acetate and hexane as the developing solvent).

PREPARATION 35 2 -Amino -1-(3,5-di-t-butyl-4-hydroxyphenyl)ethanol

A mixture comprising 44 g of 3,5-di-t-butyl-4-hydroxybenzaldehyde, 25 mlof trimethylsilylnitrile and a catalytic amount of zinc iodide washeated at 90° C. for 1 hour, whilst stirring. The reaction mixture wasthen added dropwise to a mixture of 16 g of lithium aluminum hydride and600 ml of tetrahydrofuran, whilst ice-cooling, and the resulting mixturewas stirred for 2 hours, whilst ice-cooling. At the end of this time, 16ml of water, 16 ml of a 15% w/v aqueous solution of sodium hydroxide and50 ml of water were added to the mixture, in that order. Insolublematerials were filtered off, and the filtrate was concentrated byevaporation under reduced pressure. The resulting residue was purifiedby column chromatography through silica gel, using a 20:20:1 by volumemixture of ethyl acetate, ethanol and triethylamine as the eluent, andby recrystallization from ethyl acetate, to give the title compound ascrystals, melting at 137°-140° C.

PREPARATION 36 Methyl 4-(2-oxopropoxy) mandelate

100 ml of a 10% w/w solution of trimethylsilyldiazomethane in hexanewere added dropwise, whilst ice-cooling, to a solution of 12.38 g of4-hydroxymandelic acid in a mixture of 150 ml of tetrahydrofuran and 30ml of methanol, and the resulting mixture was stirred at roomtemperature for 1 hour, after which the solvent was removed bydistillation under reduced pressure, and the resulting residue was mixedwith 250 ml of dimethylformamide, 25.2 g of bromoacetone and 25.4 g ofpotassium carbonate. The reaction mixture was then worked up in asimilar manner to that described in Preparation 3, to give the titlecompound having an Rf=0.39 (thin layer chromatography over silica gel,using a 1:1 by volume mixture of hexane and ethyl acetate as thedeveloping solvent).

PREPARATION 37 2-[4-(2 -Oxopropoxy)phenyl]ethyl acetate

1.96 g of acetic anhydride were added, whilst ice-cooling, to a mixtureof 3.1 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared as described inPreparation 7), 50 ml of anhydrous tetrahydrofuran and 2.53 g ofpyridine, and the resulting mixture was stirred at room temperature for3.5 hours. At the end of this time, 12.5 g of pyridine and 9.8 g ofacetic anhydride were added, whilst ice-cooling, and the mixture wasallowed to stand at room temperature for 1 day, after which the solventwas removed by distillation under reduced pressure, and the residue wasmixed with water and then extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate, and the solvent was removed bydistillation under reduced pressure, to give the title compound havingan Rf=0.71 (thin layer chromatography over silica gel, using a 1:1 byvolume mixture of ethyl acetate and hexane as the developing solvent).

PREPARATION 38

Dimethyl 4-(2-oxopropoxy)phenylmalonate

Following a procedure similar to that described in Preparation 3, butusing 0.5 g of dimethyl 4-hydroxyphenylmalonate, 0.612 g ofbromoacetone, 0.616 g of potassium carbonate and 90 ml ofdimethylformamide, and then purifying the reaction product by columnchromatography through silica gel, using a 2:3 by volume mixture ofethyl acetate and hexane as the eluent, the title compound was obtainedhaving an Rf=0.37 (thin layer chromatography over silica gel, using a2:3 by volume mixture of ethyl acetate and hexane as the developingsolvent).

PREPARATION 39

2 -Amino-1-(3,5-dichlorophenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 10 g of 3,5-dichlorobenzaldehyde, 6.23 g of trimethylsilylnitrile,a catalytic amount of zinc iodide, 5.4 g of lithium aluminum hydride and200 ml of tetrahydrofuran, and then purifying the reaction product bycolumn chromatography through silica gel, using a 2:1 by volume mixtureof ethyl acetate and ethanol as the eluent, the title compound wasobtained having an Rf=0.19 (thin layer chromatography over silica gel,using a 10:3:1 by volume mixture of ethyl acetate, ethanol andtriethylamine as the developing solvent) and melting at 66° C.

PREPARATION 40 2-Amino-1-(3-chloro-4-fluorophenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 10 g of 3-chloro-4-fluorobenzaldehyde, 6.89 g oftrimethylsilylnitrile, a catalytic amount of zinc iodide, 5.99 g oflithium aluminum hydride and 200 ml of tetrahydrofuran, and thenpurifying the reaction product by column chromatography through silicagel, using a 2:1 by volume mixture of ethyl acetate and ethanol as theeluent, the title compound was obtained having an Rf=0.21 (thin layerchromatography over silica gel, using a 10:3:1 by volume mixture ofethyl acetate, ethanol and triethylamine as the developing solvent).

PREPARATION 41 2 -Amino-1-(3-bromophenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 25 g of 3-bromobenzaldehyde, 14.78 g of trimethylsilylnitrile, acatalytic amount of zinc iodide, 13.2 g of lithium aluminum hydride and400 ml of tetrahydrofuran, and then purifying the reaction product bycolumn chromatography through silica gel, using a 2:1 by volume mixtureof ethyl acetate and ethanol as the eluent, the title compound wasobtained having an Rf=0.22 (thin layer chromatography over silica gel,using a 10:3:1 by volume mixture of ethyl acetate, ethanol andtriethylamine as the developing solvent).

PREPARATION 42 2-Amino-1-(3-trifluoromethylphenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 25 g of 3-trifluoromethylbenzaldehyde, 15.71 g oftrimethylsilylnitrile, a catalytic amount of zinc iodide, 12.8 g oflithium aluminum hydride and 400 ml of tetrahydrofuran, and thenpurifying the reaction product by column chromatography through silicagel, using a 2:1 by volume mixture of ethyl acetate and ethanol as theeluent, the title compound was obtained as cryatals, melting at 72° C.and having an Rf=0.25 (thin layer chromatography over silica gel, usinga 10:3:1 by volume mixture of ethyl acetate, ethanol and triethylamineas the developing solvent).

PREPARATION 43 2 -Amino-1-(3-methoxyphenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 28 g of 3-methoxybenzaldehyde, 22.92 g of trimethylsilylnitrile, acatalytic amount of zinc iodide, 19.92 g of lithium aluminum hydride and400 ml of tetrahydrofuran, and then purifying the reaction product bycolumn chromatography through silica gel, using a 2:1 by volume mixtureof ethyl acetate and ethanol as the eluent, the title compound wasobtained having an Rf=0.18 (thin layer chromatography over silica gel,using a 10:3:1 by volume mixture of ethyl acetate, ethanol andtriethylamine as the developing solvent).

PREPARATION 44 2-Amino-1-(3-methylphenyl)ethanol

Following a procedure similar to that described in Preparation 8, butusing 25.75 g of 3-methylbenzaldehyde, 23.35 g of trimethylsilylnitrile,a catalytic amount of zinc iodide, 20.3 g of lithium aluminum hydrideand 400 ml of tetrahydrofuran, and then purifying the reaction productby column chromatography through silica gel, using a 2:1 by volumemixture of ethyl acetate and ethanol as the eluent, the title compoundwas obtained having an Rf=0.22 (thin layer chromatography over silicagel, using a 10:3:1 by volume mixture of ethyl acetate, ethanol andtriethylamine as the developing solvent).

PREPARATION 45 3-Chloromandelic acid

A mixture of 158 g of 3-chlorobenzaldehyde, 111.6 g oftrimethylsilylnitrile and a catalytic amount of zinc iodide was heatedat 90° C. for 2 hours, with stirring. The reaction mixture wasice-cooled, and 350 ml of concentrated aqueous hydrochloric acid wereadded to it. The resulting mixture was then heated under reflux for 1hour, after which it was mixed with water and with ethyl acetate. Theethyl acetate layer was separated and mixed with a 30% w/v aqueoussolution of sodium hydroxide. The aqueous layer was separated, washedthree times with ethyl acetate and then acidified with concentratedaqueous hydrochloric acid, after which it was extracted with ethylacetate. The extract was washed with water and dried over anhydroussodium sulfate. The solvent was then removed by distillation underreduced pressure, to give the title compound as crystals, melting at110°-114° C.

PREPARATION 46 (R)-3-Chloromandelic acid and (S)-3-chloromandelic acid

A mixture of 100 g of 3-chloromandelic acid (prepared as described inPreparation 45) and 32.7 g of (R)-(+)-1-phenethylamine was dissolved inand recrystallized from a mixture of methanol and diethyl ether. Theresulting crystals were collected by filtration, recrystallized threetimes from a mixture of methanol and diethyl ether and mixed withaqueous hydrochloric acid. The mixture was then extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate, and thesolvent was removed by distillation under reduced pressure, to give(R)-3-chloromandelic acid as crystals, melting at 102°-105° C.

[α]_(D) ²³ -153.7° (c=1.026, chloroform)

Hydrochloric acid was added to the filtrate obtained as described above,and the mixture was extracted with ethyl acetate. The extract was driedover anhydrous sodium sulfate, and the solvent was removed bydistillation under reduced pressure. The resulting residue was mixedwith 32.7 g of (S)-(-)-1-phenethylamine and was recrystallized threetimes from a mixture of methanol and diethyl ether, to give(S)-3-chloromandelic acid as crystals, melting at 101°-104° C.

[α]_(D) ²³ +151.9° (c=1.008, chloroform).

PREPARATION 47 Methyl (R)-3-chloromandelate

18.3 g of a 10% w/v solution of trimethylsilyldiazomethane in hexanewere added dropwise to a solution of 28 g of (R)-3-chloromandelic acid(prepared as described in Preparation 46) in a mixture of 300 ml ofmethanol and 700 ml of benzene, and the resulting mixture was stirredfor 1 hour. At the end of this time, the solvent was removed bydistillation under reduced pressure, to give the title compound having[α]_(D) ²³ -119.3° (c=1.00, chloroform) and an Rf=0.36 (thin layerchromatography over silica gel, using a 1:5 by volume mixture of ethylacetate and hexane) as a crude product.

PREPARATION 48 Methyl(R)-=-t-butyldimethylsilyloxy-3-chlorophenylacetate

A solution of 31.6 g of t-butyldimethylsilyl chloride in 200 ml ofdimethylformamide was added dropwise, whilst ice-cooling, to a solutionof 28 g of methyl (R)-3-chloromandelate (prepared as described inPreparation 47) and 28.5 g of imidazole in 300 ml of dimethylformamide,and the resulting mixture was stirred at the same temperature for 30minutes, after which it was allowed to stand overnight at 40° C. At theend of this time, the reaction mixture was concentrated by evaporationunder reduced pressure, and the residue was mixed with water and ethylacetate. The ethyl acetate layer was separated and dried over anhydroussodium sulfate, and then the solvent was removed by distillation underreduced pressure. The resulting residue was purified by columnchromatography through silica gel, using a 1:15 by volume mixture ofethyl acetate and hexane as the eluent, to give the title compound ascrystals, melting at 36°-38° C. [α]_(D) ²³ -39.1° (c=1.014, chloroform).

PREPARATION 49(R)-α-t-Butyldimethylsilyloxy-α-(3-chlorophenyl)-acetaldehyde

A solution of 26 g of methyl(R)-α-t-butyldimethylsilyloxy-3-chlorophenylacetate (prepared asdescribed in Preparation 48) in a mixture of 1000 ml of anhydrous hexaneand 500 ml of dry toluene was cooled to -60° C., and then 124 ml of a 1Msolution of diisobutylaluminum hydride in hexane were added dropwise tothe cooled solution. The resulting mixture was stirred at the sametemperature for 3 hours, after which 10 ml of water were added to it,and the temperature of the mixture was gradually allowed to rise to roomtemperature. The reaction mixture was then mixed with water and ethylacetate, after which it was stirred for 30 minutes. Insoluble materialswere filtered off using a Celite (trade mark) filter aid, and the ethylacetate layer was separated from the filtrate and dried over anhydroussodium sulfate. The ethyl acetate solvent was removed by distillationunder reduced pressure, and the residue was purified by columnchromatography through silica gel, using a 1:60 by volume mixture ofethyl acetate and hexane as the eluent, to give the title compoundhaving an Rf=0.36 (thin layer chromatography over silica gel, using a1:60 by volume mixture of ethyl acetate and hexane as the developingsolvent).

PREPARATION 50 N-[2-(4-Methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethanamine

Following a procedure similar to that described in Preparation 29, butusing 5.2 g of(R)-α-t-butyl-dimethylsilyloxy-α-(3-chlorophenyl)acetaldehyde (preparedas described in Preparation 49), 4.24 g of methyl4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described inPreparation 27), 50 ml of absolute methanol and 3.4 g of sodiumcyanoborohydride, the title compound was obtained having an Rf=0.20(thin layer chromatography over silica gel, using a 1:4 by volumemixture of ethyl acetate and hexane as the developing solvent).

[α]_(D) ²³ -34.7° (c=1.024, chloroform).

PREPARATION 51 5-{4-[2(R)-Amino-1-propoxy]benzyl}thiazolidine-2,4-dionetrifluoroacetate

51(a) 5-(4-Acetoxybenzylidene)thiazolidine-2,4-dione

A mixture comprising 200 g of p-hydroxybenzaldehyde, 229 g ofthiazolidine-2,4-dione, 280 g of sodium acetate and 660 ml ofdimethylacetamide was stirred at 150° for 1 hour. It was then cooled,and 540 ml of dimethylacetamide and 370 ml of acetic anhydride wereadded to the reaction mixture. The resulting mixture was then stirred at50° C. for 1.5 hours, after which it was poured into water. The solidwhich precipitated was collected by filtration, washed with water, anddried over anhydrous sodium sulfate, to give the title compound.

51(b) 5-(4-Acetoxybenzyl)thiazolidine-2,4-dione

2.0 g of 5-(4-acetoxybenzylidene)thiazolidine-2,4-dione [prepared asdescribed in step (a) above] was dissolved in 80 ml of acetic acid andwas hydrogenated by passing hydrogen at atmospheric pressure through thesolution at 90° C. for 5 hours in the presence of 2.0 g of 10% w/wpalladium-on-charcoal. At the end of this time, the catalyst wasfiltered off, and the filtrate was diluted with toluene. The acetic acidsolvent was then removed by distillation as a toluene azeotrope. Thecrystals which separated out on adding toluene and hexane to theconcentrate were collected by filtration and dried to give the titlecompound.

51(c) 5-(4-Acetoxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione

3.43 g of trimethylamine were added to a solution of 9.0 g of5-(4-acetoxybenzyl)thiazolidine-2,4-dione [prepared as described in step(b) above] in 70 ml of methylene chloride, and a solution of 9.45 g oftriphenylmethyl chloride in 30 ml of methylene chloride was addeddropwise to the resulting mixture. The mixture was then stirred at roomtemperature for 1 hour, after which it was allowed to stand overnight atthe same temperature. At the end of this time, the reaction mixture wasmixed with water and ethyl acetate, and the organic layer was separated,washed with a saturated aqueous solution of sodium chloride, and driedover anhydrous sodium sulfate. The crystals which separated out ondistilling off the solvent under reduced pressure, were washed with amixture of hexane and ethyl acetate and dried, to give the titlecompound.

51 (d) 5-(4-Hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione

A solution of 2.99 g of a 28% w/v methanolic solution of sodiummethoxide in 10 ml of methanol was added dropwise, whilst ice-cooling,to a solution of 7.86 g of5-(4-acetoxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared asdescribed in step (c) above] in 70 ml of toluene, and the resultingmixture was stirred at room temperature for 1 hour, after which it wasallowed to stand overnight at the same temperature. The pH of thereaction mixture was then adjusted to a value of 4 by the addition of 1Naqueous hydrochloric acid, and the mixture was extracted with ethylacetate. The extract was washed with water and dried over anhydroussodium sulfate. The solvent was then removed by distillation underreduced pressure, and the crystals which appeared in the residue werecollected, washed with hexane and dried, to give the title compound.

51(e) 5-{4- [2(R)-t-Butoxycarbonylaminopropoxy]-benzyl}-3-triphenylmethylthiazolidine-2,4-dione

13.2 g of diethyl azodicarboxylate were added dropwise to a solution of20.7 g of triphenylphosphine in 300 ml of benzene and the mixture wasstirred at room temperature for 30 minutes. At the end of this time,35.0 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione[prepared as described in step (d) above] were added to the mixture, andthe resulting mixture was stirred at room temperature for 1 hour. 13.2 gof (R)-2-t-butoxycarbonylamino-1-propanol were added to the mixture,which was then allowed to stand overnight. At the end of this time, 40.9g of triphenylphosphine, 23.68 ml of diethyl azodicarboxylate and 33 gof (R)-2-t-butoxycarbonylamino-1-propanol were added to the reactionmixture, in that order, in 3 or 4 separate portions, and the mixture wasthen stirred for 2 days. After this time, the benzene solvent wasremoved from the reaction mixture by distillation under reducedpressure, and the residue was purified by column chromatography throughsilica gel, using a 1: 3 by volume mixture of ethyl acetate and hexaneas the eluent, to give 30 g of the title compound as crystals, meltingat 153°-157° C.

[α]_(D) ²³ +19.5° (c=1.000, chloroform).

51(f) 5-{4-[2(R) -Aminopropoxy]benzyl}thiazolidine-2,4-dionetrifluoroacetate

500 ml of trifluoroacetic acid were added dropwise, whilst ice-cooling,to a solution of 85.5 g of5-{4-[2(R)-t-butoxycarbonylaminopropoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione[prepared as described in step (e) above] in 700 ml of methylenechloride, and the resulting mixture was stirred at room temperature for4 hours. At the end of this time, the reaction mixture was freed fromthe methylene chloride solvent and the trifluoroacetic acid bydistillation under reduced pressure, and a mixture of benzene and asmall amount of ethyl acetate was added to the residue. The crystalswhich precipitated were collected by filtration and were recrystallizedfrom a mixture of methanol and ethyl acetate, to give the title compoundas crystals, melting at 162°-166° C.

[α]_(D) ²³ -13.0° (c=0.885, methanol)

PREPARATION 525-[4-{2(R)-[2(R)-(3-chlorophenyl)-2-t-butyldimethylsilyloxyethylamino]propoxy}benzyl]-thiazolidine-2,4-dione

A mixture comprising 36.5 g of5-{4-[2(R)-aminopropoxy]benzyl}thiazolidine-2,4-dione trifluoroacetate(prepared as described in Preparation 51), 98.4 g of(R)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared asdescribed in Preparation 25) and 400 ml of absolute methanol was stirredat room temperature for 2.5 hours and then 29.0 g of sodiumcyanoborohydride were added in portions to the mixture, whilst coolingit in an ice-sodium chloride bath. The reaction mixture was then allowedto stand overnight at room temperature, after which the methanol solventwas removed by distillation under reduced pressure. The resultingresidue was mixed with water and ethyl acetate. The ethyl acetate layerwas separated, washed with an aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The ethyl acetate solvent was thenwas removed by distillation under reduced pressure, and the resultingresidue was purified by column chromatography through silica gel, usinga 2:1 by volume mixture of ethyl acetate and hexane as the eluent, togive the title compound.

[α]_(D) ²³ -26.3° (c=0 988 chloroform).

PREPARATION 532-{2-[4-(2Methoxycarbonylethenyl)phenoxy]-1-methylethyl}amino-1-(3-chlorophenyl)ethanol

A solution of 6.07 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared asdescribed in Preparation 8) and 6.5 g of methyl 4-(2-oxopropoxy)cinnamate (prepared as described in Preparation 4) in 100 ml of benzenewas heated under reflux for 3.5 hours and the water formed during thereaction was removed continuously. At the end of this time, the reactionmixture was freed from the benzene used as solvent by distillation underreduced pressure, and the resulting residue was dissolved in 100 ml ofabsolute methanol. 3 g of sodium borohydride were added to thissolution, whilst ice-cooling, and the resulting mixture was stirred atroom temperature overnight and then at 60° C. for 5 hours. The reactionmixture was then concentrated by evaporation under reduced pressure, andthe concentrate was extracted with ethyl acetate. The extract was washedwith water and was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under reduced pressure, and the resultingresidue was purified by column chromatography through silica gel, usinga 10:1 by volume mixture of ethyl acetate and ethanol as an eluent togive two fractions. The product thus obtained was recrystallized from amixture of ethyl acetate and hexane, to give the title compound, meltingat 97°-103 ° C.

PREPARATION 54 Dimethyl 4-(2-oxopropoxy) phthalate

Following a procedure similar to that described in Preparation 3, butusing 10.5 g of dimethyl 4-hydroxyphthalate, 13.7 g of bromoacetone, 14g of potassium carbonate and 150 ml of dimethylformamide, the titlecompound was obtained as an oil, having an Rf=0.48 (thin layerchromatography over silica gel, using a 1:1 by volume mixture of haexaneand ethyl acetate as the developing solvent).

PREPARATION 55 Dimethyl 4-(2-oxopropoxy) isophthalate

Following a procedure similar to that described in Preparation 3, butusing 10.5 g of dimethyl 4-hydroxyisophthalate, 15 g of bromoacetone, 17g of potassium carbonate and 100 ml of dimethylformamide, and thenpurifying the reaction product by column chromatography through silicagel, using a 2:1 by volume mixture of hexane and ethyl acetate as theeluent, the title compound was obtained as crystals, melting at115°-116° C.

We claim:
 1. A compound of formula (I): ##STR25## wherein: R⁰ representsa hydrogen atom, a methyl group or a hydroxymethyl group;R¹ represents asubstituted alkyl group having from 1 to 12 carbon atoms, which group issubstituted by at least one substituent selected from substituents A,defined below; R² and R³ are independently selected from the groupconsisting of: hydrogen atoms; halogen atoms; hydroxy groups; alkoxygroups having from 1 to 5 carbon atoms; carboxy groups; alkoxycarbonylgroups having from 2 to 7 carbon atoms; alkyl groups having from 1 to 5carbon atoms; nitro groups; haloalkyl groups having from 1 to 4 carbonatoms; and substituted alkyl groups which have from 1 to 12 carbon atomsand which are substituted by at least one substituent selected fromsubstituents A, defined below; X represents an oxygen or sulfur atom;and Ar represents a group of formula (II) or (III): ##STR26## wherein:R⁴ represents a hydrogen atom, a halogen atom, a hydroxy group, ahydroxymethyl group, an alkoxy group having from 1 to 5 carbon atoms, analkyl group having from 1 to 5 carbon atoms, an aliphatic carboxylicacyloxy group having from 1 to 6 carbon atoms, a nitro group, a cyanogroup, an aralkyloxy group, in which the aralkyl part is as definedbelow, an aryloxy group in which the aryl part is as defined below, anaryl group as defined below or a haloalkyl group having from 1 to 4carbon atoms; R⁵ represents a hydrogen atom, a halogen atom, a hydroxygroup, an alkoxy group having from 1 to 5 carbon atoms, an alkyl grouphaving from 1 to 5 carbon atoms or a nitro group; and R⁶ represents ahydrogen atom, a halogen atom, a hydroxy group, an alkoxy group havingfrom 1 to 5 carbon atoms or an alkyl group having from 1 to 5 carbonatoms; said aralkyl part is an alkyl group which has from 1 to 3 carbonatoms and which is substituted by 1 or 2 aryl groups as defined below:said aryl groups are carbocyclic aryl groups which have from 6 to 10ring carbon atoms and which are unsubstituted or are substituted by atleast one substituent selected from the group consisting of substituentsB, defined below; said substituents A are 2,4-dioxothiazolidin-5-ylgroups; and said substituents B are selected from the group consistingof halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxygroups having from 1 to 3 carbon atoms, nitro groups, haloalkyl groupshaving from 1 to 4 carbon atoms and hydroxy groups;or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein R⁰represents a hydrogen atom or a methyl group.
 3. The compound of claim1, wherein R⁰ represents a hydrogen atom.
 4. The compound of claim 1,wherein R¹ represents a substituted alkyl group having from 1 to 12carbon atoms and substituted by at least 1 and no more than 82,4-dioxothiazolidin-5-yl groups.
 5. The compound of claim 1, wherein R¹represents a substituted alkyl group which has from 1 to 12 carbon atomsand which is substituted by at least 1 and no more than 62,4-dioxothiazolidin-5-yl groups.
 6. The compound of claim 1, wherein R¹represents a substituted alkyl group which has from 1 to 6 carbon atomsand which is substituted by at least 1 and no more than 62,4-dioxothiazolidin-5-yl groups.
 7. The compound of claim 1, wherein R¹represents a substituted alkyl group which has from 1 to 3 carbon atomsand which is substituted by at least 1 and no more than 42,4-dioxothiazolidin-5yl groups.
 8. The compound of claim 1, wherein R¹represents an alkyl group which has from 1 to 3 carbon atoms and whichis substituted by 1 or 2 2,4-dioxothiazolidin-5-yl groups.
 9. Thecompound of claim 1, wherein R¹ represents a methoxycarbonylmethyl,2,4-dioxothiazolidin-5-yl-methyl group.
 10. The compound of claim 1,wherein R² and R³ are the same or different and each represents ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a methoxy group, an ethoxy group, a carboxy group, analkoxycarbonyl group having from 2 to 7 carbon atoms, an alkyl grouphaving from 1 to 5 carbon atoms, a nitro group, a trifluoromethyl groupor a substituted alkyl group having from 1 to 12 carbon atoms andsubstituted by at least 1 and no more than 8 2,4-dioxothiazolidin-5-ylgroup.
 11. The compound of claim 1, wherein R² represents a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group,a methoxy group, an ethoxy group, an alkyl group having from 1 to 4carbon atoms or a nitro group.
 12. The compound of claim 1, wherein R²represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxygroup, a methoxy group, or an alkyl group having from 1 to 4 carbonatoms.
 13. The compound of claim 1, wherein R² represents a hydrogenatom, a chlorine atom, a hydroxy group, a methoxy group or a methylgroup.
 14. The compound of claim 1, wherein R² represents a hydrogenatom, a chlorine atom or a hydroxy group.
 15. The compound of claim 1,wherein R² represents a hydrogen atom or a chlorine atom.
 16. Thecompound of claim 1, wherein R² represents a hydrogen atom.
 17. Thecompound of claim 1, wherein R³ represents a hydrogen atom, a fluorineatom, a chlorine atom, a hydroxy group, a methoxy group, a methyl groupor a t-butyl group.
 18. The compound of claim 1, wherein R³ represents ahydrogen atom, a chlorine atom, a hydroxy group, a methoxy group or amethyl group.
 19. The compound of claim 1, wherein R³ represents ahydrogen atom or a methyl group.
 20. The compound of claim 1, wherein R³represents a hydrogen atom.
 21. The compound of claim 1, wherein R⁴represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromineatom, a hydroxy group, a hydroxymethyl group, a methoxy group, an ethoxygroup, an alkyl group having from 1 to 5 carbon atoms, an acetoxy group,a nitro group, a cyano group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group.
 22. The compound of claim 1,wherein R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group,an ethoxy group, an alkyl group having from 1 to 4 carbon atoms, anacetoxy group, a nitro group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group.
 23. The compound of claim 1,wherein R⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a methoxy group, an alkyl group having from 1 to 4carbon atoms, a phenoxy group or a trifluoromethyl group.
 24. Thecompound of claim 1, wherein R⁵ represents a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a hydroxy group, a methoxy group,an alkyl group having from 1 to 5 carbon atoms or a nitro group.
 25. Thecompound of claim 1, wherein R⁵ represents a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a hydroxy group, a methoxy groupor an alkyl group having from 1 to 4 carbon atoms.
 26. The compound ofclaim 1, wherein R⁵ represents a hydrogen atom, a chlorine atom, amethoxy group or an alkyl group having from 1 to 4 carbon atoms.
 27. Thecompound of claim 1, wherein R⁶ represents a hydrogen atom, a fluorineatom, a chlorine atom, a hydroxy group, a methoxy group or a methylgroup.
 28. The compound of claim 1, wherein R⁶ represents a hydrogenatom, a hydroxy group, a methoxy group or a methyl group.
 29. Thecompound of claim 1, wherein R⁶ represents a hydrogen atom, a hydroxygroup or a methoxy group.
 30. The compound of claim 1, wherein Arrepresents a phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-bromophenyl, 3-fluorophenyl, 3-phenoxyphenyl, 3-methylphenyl,3-methoxyphenyl, 3,5-dichlorophenyl, 3,5-di-t-butyl-4-hydroxyphenyl,3,4,5-trimethoxyphenyl, 3-trifluoromethylphenyl,3-chloro-4-fluorophenyl, 1-naphthyl or 2-naphthyl group.
 31. Thecompound of claim 1, wherein Ar represents a phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl,3-methylphenyl, 3-methoxyphenyl, 3,5-di-t-butyl-4-hydroxyphenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl or 2-naphthyl group.32. The compound of claim 1, wherein Ar represents a phenyl,3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl,3-chloro-4-fluorophenyl or 2-naphthyl group.
 33. The compound of claim1, wherein X represents an oxygen atom.
 34. The compound of claim 1,wherein:R⁰ represents a hydrogen atom, a methyl group or a hydroxymethylgroup; R¹ represents a substituted alkyl group having from 1 to 12carbon atoms and substituted by at least 1 and no more than 8substituents selected from the group consisting of substituents A¹defined below; R² and R³ are the same or different and each represents ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a methoxy group, an ethoxy group, a carboxy group, analkoxycarbonyl group having from 2 to 7 carbon atoms, an alkyl grouphaving from 1 to 5 carbon atoms, a nitro group, a trifluoromethyl groupor a substituted alkyl group having from 1 to 12 carbon atoms andsubstituted by at least 1 and no more than 8 2,4-dioxothiazolidin-5-ylgroups; X represents an oxygen or sulfur atom; Ar represents a group offormula (II) or (III), defined in claim 1; R⁴ represents a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group,a hydroxymethyl group, a methoxy group, an ethoxy group, an alkyl grouphaving from 1 to 5 carbon atoms, an acetoxy group, a nitro group, acyano group, a benzyloxy group, a phenoxy group, a phenyl group or atrifluoromethyl group; R⁵ represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, a hydroxy group, a methoxy group, analkyl group having from 1 to 5 carbon atoms or a nitro group; and R⁶represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxygroup, a methoxy group or a methyl group.
 35. The compound of claim 1,wherein:R⁰ represents a hydrogen atom or a methyl group; R¹ represents asubstituted alkyl group which has from 1 to 12 carbon atoms and which issubstituted by at least 1 and no more than 6 2,4-dioxothiazolidin-5ylgroups; R² represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a hydroxy group, a methoxy group, an ethoxy group, analkyl group having from 1 to 4 carbon atoms or a nitro group; R³represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxygroup, a methoxy group, a methyl group or a t-butyl group; X representsan oxygen or sulfur atom; and Ar represents a group of formula (II) or(III), defined in claim 1; R⁴ represents a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a hydroxy group, a hydroxymethylgroup, a methoxy group, an ethoxy group, an alkyl group having from 1 to4 carbon atoms, an acetoxy group, a nitro group, a benzyloxy group, aphenoxy group, a phenyl group or a trifluoromethyl group; R⁵ representsa hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a methoxy group or an alkyl group having from 1 to 4carbon atoms; and R⁶ represents a hydrogen atom, a fluorine atom, achlorine atom, a hydroxy group, a methoxy group or a methyl group. 36.The compound of claim 1, wherein:R⁰ represents a hydrogen atom or amethyl group; R¹ represents a substituted alkyl group which has from 1to 6 carbon atoms and which is substituted by at least 1 and no morethan 6 2,4-dioxothiazolidin-5yl groups; R² represents a hydrogen atom, afluorine atom, a chlorine atom, a bromine atom, a hydroxy group, amethoxy group, an ethoxy group or an alkyl group having from 1 to 4carbon atoms; R³ represents a hydrogen atom, a fluorine atom, a chlorineatom, a hydroxy group, a methoxy group, a methyl group or a t-butylgroup; X represents an oxygen or sulfur atom; Ar represents a group offormula (II) or (III), defined in claim 1; R⁴ represents a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group,a hydroxymethyl group, a methoxy group, an ethoxy group, an alkyl grouphaving from 1 to 4 carbon atoms, an acetoxy group, a nitro group, abenzyloxy group, a phenoxy group, a phenyl group or a trifluoromethylgroup; R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a hydroxy group, a methoxy group or an alkyl grouphaving from 1 to 4 carbon atoms; and R⁶ represents a hydrogen atom, afluorine atom, a chlorine atom, a hydroxy group, a methoxy group or amethyl group.
 37. The compound of claim 1, wherein:R⁰ represents ahydrogen atom or a methyl group; R¹ represents a substituted alkyl groupwhich has from 1 to 3 carbon atoms and which is substituted by at least1 and no more than 2,4- dioxothiazolidin-5yl groups; R² represents ahydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, amethoxy group and an alkyl group having from 1 to 4 carbon atoms; R³represents a hydrogen atom, a chlorine atom, a hydroxy group, a methoxygroup or a methyl group; X represents an oxygen atom; Ar represents agroup of formula (II) or (III), defined in claim 1; R⁴ represents ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a hydroxymethyl group, a methoxy group, an ethoxy group,an alkyl group having from 1 to 4 carbon atoms, an acetoxy group, anitro group, a benzyloxy group, a phenoxy group, a phenyl group or atrifluoromethyl group; R⁵ represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, a hydroxy group, a methoxy group or analkyl group having from 1 to 4 carbon atoms and R⁶ represents a hydrogenatom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy groupor a methyl group.
 38. The compound of claim 1, wherein:R⁰ represents ahydrogen atom or a methyl group; R¹ represents a substituted alkyl groupwhich has from 1 to 3 carbon atoms and which is substituted by at least1 and no more than 4 2,4-dioxothiazolidin-5-yl groups; R² represents ahydrogen atom, a chlorine atom, a hydroxy group, a methoxy group, or amethyl group; R³ represents a hydrogen atom or a methyl group; Xrepresents an oxygen atom; Ar represents a group of formula (II) or(III), defined in claim 1; R⁴ represents a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a hydroxy group, a hydroxymethylgroup, a methoxy group, an ethoxy group, an alkyl group having from 1 to4 carbon atoms, an acetoxy group, a nitro group, a benzyloxy group, aphenoxy group, a phenyl group or a trifluoromethyl group; R⁵ representsa hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a methoxy group or an alkyl group having from 1 to 4carbon atoms; R⁶ represents a hydrogen atom, a hydroxy group, a methoxygroup or a methyl group.
 39. The compound of claim 1, wherein:R⁰represents a hydrogen atom; R¹ represents a substituted alkyl groupwhich has from 1 to 3 carbon atoms and which is substituted by at least1 and no more than 4 2,4-dioxothiazolidin-5yl groups; R² represents ahydrogen atom, a chlorine atom, a hydroxy group, a methoxy group or amethyl group hydroxymethyl group and R³ represents a hydrogen atom; Xrepresents an oxygen atom; Ar represents a group of formula (II) or(III), defined in claim 1; R⁴ represents a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a methoxy group, an alkyl grouphaving from 1 to 4 carbon atoms, a phenoxy group or a trifluoromethylgroup; R⁵ represents a hydrogen atom, a chlorine atom, a methoxy groupor an alkyl group having from 1 to 4 carbon atoms; R⁶ represents ahydrogen atom, a hydroxy group or a methoxy group.
 40. The compound ofclaim 1, wherein:R⁰ represents a hydrogen atom; R¹ represents an alkylgroup which has from 1 to 3 carbon atoms and which is substituted by 1or 2 2,4-dioxothiazolidin-5yl groups; R² represents a hydrogen atom, achlorine atom or a hydroxy group; R³ represents a hydrogen atom; Xrepresents an oxygen atom; and Ar represents a phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl,3-phenoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,5-dichlorophenyl,3,5-di-t-butyl-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 1-naphthyl or2-naphthyl group.
 41. The compound of claim 1, wherein:R⁰ represents ahydrogen atom; R¹ represents a 2,4-dioxothiazolidin-5-yl-methyl group;R² represents a hydrogen atom or a chlorine atom; R³ represents ahydrogen atom; X represents an oxygen atom; and Ar represents a phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl,3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl,3,5-di-t-butyl-4-hydroxyphenyl, 3-trifluoromethylphenyl,3-chloro-4-fluorophenyl or 2-naphthyl group.
 42. The compound of claim1, wherein:R⁰ represents a hydrogen atom; R¹ represents a2-methoxycarbonylethyl, bis(methoxycarbonyl)-methyl, hydroxymethyl,2-hydroxyethyl, 2-methoxy- or 2,4-dioxothiazolidin-5-yl-methyl group; R²represents a hydrogen atom; R³ represents a hydrogen atom; X representsan oxygen atom; and Ar represents a phenyl, 3-chlorophenyl,3-bromophenyl, 3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl or2-naphthyl group.
 43. The compound of claim 1, selected from the groupconsisting of5-[4-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dioneand salts thereof.
 44. The compound of claim 1, selected from the groupconsisting of5-[4-{2-[2-(3-trifluoromethylphenyl)-2hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dioneand salts thereof.
 45. A pharmaceutical composition for the treatment orprophylaxis of diabetes, obesity, hyperlipemia, hyperglycemia,complications of diabetes, obesity-related hypertension andosteoporosis, which composition comprises an effective amount of anactive compound in admixture with a pharmaceutically acceptable carrieror diluent, wherein the active compound is selected from the groupconsisting of compounds of formula (I) as claimed in claim
 1. 46. Thecomposition of claim 45, wherein:R⁰ represents a hydrogen atom, a methylgroup or a hydroxymethyl group; R¹ represents a substituted alkyl grouphaving from 1 to 12 carbon atoms and substituted by at least 1 and nomore than 8 2,4-dioxothiazolidin-5-yl groups; R² and R³ are the same ordifferent and each represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, a hydroxy group, a methoxy group, anethoxy group, a carboxy group, an alkoxycarbonyl group having from 2 to7 carbon atoms, an alkyl group having from 1 to 5 carbon atoms, a nitrogroup, a trifluoromethyl group or a substituted alkyl group having from1 to 12 carbon atoms and substituted by at least 1 and no more than 82,4-dioxothiazolidin-5yl groups; X represents an oxygen or sulfur atom;Ar represents a group of formula (II) or (III), defined in claim 45; R⁴represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromineatom, a hydroxy group, a hydroxymethyl group, a methoxy group, an ethoxygroup, an alkyl group having from 1 to 5 carbon atoms, an acetoxy group,a nitro group, a cyano group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group; R⁵ represents a hydrogen atom,a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, amethoxy group, an alkyl group having from 1 to 5 carbon atoms or a nitrogroup; and R⁶ represents a hydrogen atom, a fluorine atom, a chlorineatom, a hydroxy group, a methoxy group or a methyl group.
 47. Thecomposition of claim 45, wherein:R⁰ represents a hydrogen atom or amethyl group; R¹ represents a substituted alkyl group which has from 1to 12 carbon atoms and which is substituted by at least 1 and no morethan 6 2,4-dioxothiazolidin-5-yl groups; R² represents a hydrogen atom,a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, amethoxy group, an ethoxy group, an alkyl group having from 1 to 4 carbonatoms or a nitro group, R³ represents a hydrogen atom, a fluorine atom,a chlorine atom, a hydroxy group, a methoxy group, a methyl group or at-butyl group; X represents an oxygen or sulfur atom; and Ar representsa group of formula (II) or (III), defined in claim 45; R⁴ represents ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a hydroxymethyl group, a methoxy group, an ethoxy group,an alkyl group having from 1 to 4 carbon atoms, an acetoxy group, anitro group, a benzyloxy group, a phenoxy group, a phenyl group or atrifluoromethyl group; R⁵ represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, a hydroxy group, a methoxy group or analkyl group having from 1 to 4 carbon atoms; and R⁶ represents ahydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, amethoxy group or a methyl group.
 48. The composition of claim 45,wherein:R⁰ represents a hydrogen atom or a methyl group; R¹ represents asubstituted alkyl group which has from 1 to 6 carbon atoms and which issubstituted by at least 1 and no more than 6 2,4-dioxothiazolidin-5ylgroups; R² represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a hydroxy group, a methoxy group, an ethoxy group or analkyl group having from 1 to 4 carbon atoms; R³ represents a hydrogenatom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxygroup, a methyl group or a t-butyl group.
 49. The composition of claim45, wherein:R⁰ represents a hydrogen atom or a methyl group; R¹represents a substituted alkyl group which has from 1 to 3 carbon atomsand which is substituted by at least 1 and no more than 42,4-dioxothiazolidin-5-yl groups. R² represents a hydrogen atom, afluorine atom, a chlorine atom, a hydroxy group, a methoxy group or analkyl group having from 1 to 4 carbon atoms; R³ represents a hydrogenatom, a chlorine atom, a hydroxy group, a methoxy group or a methylgroup; X represents an oxygen atom; Ar represents a group of formula(II) or (III), defined in claim 45; R⁴ represents a hydrogen atom, afluorine atom, a chlorine atom, a bromine atom, a hydroxy group, ahydroxymethyl group, a methoxy group, an ethoxy group, an alkyl grouphaving from 1 to 4 carbon atoms, an acetoxy group, a nitro group, abenzyloxy group, a phenoxy group, a phenyl group or a trifluoromethylgroup; R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a hydroxy group, a methoxy group or an alkyl grouphaving from 1 to 4 carbon atoms; and R⁶ represents a hydrogen atom, afluorine atom, a chlorine atom, a hydroxy group, a methoxy group or amethyl group.
 50. The composition of claim 45, wherein:R⁰ represents ahydrogen atom or a methyl group; R¹ represents a substituted alkyl groupwhich has from 1 to 3 carbon atoms and which is substituted by at least1 and no more than 4 2,4-dioxothiazolidin-5-yl groups; R² represents ahydrogen atom, a chlorine atom, a hydroxy group, a methoxy group or amethyl group; R³ represents a hydrogen atom or a methyl group; Xrepresents an oxygen atom; Ar represents a group of formula (II) or(III), defined in claim 45; R⁴ represents a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a hydroxy group, a hydroxymethylgroup, a methoxy group, an ethoxy group, an alkyl group having from 1 to4 carbon atoms, an acetoxy group, a nitro group, a benzyloxy group, aphenoxy group, a phenyl group or a trifluoromethyl group; R⁵ representsa hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a methoxy group or an alkyl group having from 1 to 4carbon atoms; and R⁶ represents a hydrogen atom, a hydroxy group, amethoxy group or a methyl group.
 51. The composition of claim 45,wherein:R⁰ represents a hydrogen atom; R¹ represents a substituted alkylgroup which has from 1 to 3 carbon atoms and which is substituted by atleast 1 and no more than 4 2,4-dioxothiazolidin-5yl groups; R²represents a hydrogen atom, a chlorine atom, a hydroxy group, a methoxygroup or a methyl group; R³ represents a hydrogen atom; X represents anoxygen atom; Ar represents a group of formula (II) or (III), defined inclaim 45; R⁴ represents a hydrogen atom, a fluorine atom, a chlorineatom, a bromine atom, a methoxy group, an alkyl group having from 1 to 4carbon atoms, a phenoxy group or a trifluoromethyl group; R⁵ representsa hydrogen atom, a chlorine atom, a methoxy group or an alkyl grouphaving from 1 to 4 carbon atoms; and R⁶ represents a hydrogen atom, ahydroxy group or a methoxy group.
 52. The composition of claim 45,wherein:R⁰ represents a hydrogen atom; R¹ represents an alkyl groupwhich has from 1 to 3 carbon atoms and which is substituted by 1 or 22,4-dioxothiazolidin-5yl groups; R² represents a hydrogen atom, achlorine atom or a hydroxy group; R³ represents a hydrogen atom; Xrepresents an oxygen atom; and Ar represents a phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl,3-phenoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,5-dichlorophenyl,3,5-di-t-butyl-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 1-naphthyl or2-naphthyl group.
 53. The composition of claim 45, wherein:R⁰ representsa hydrogen atom; R¹ represents a 2,4-dioxothiazolidin-5-yl-methyl group;R² represents a hydrogen atom or a chlorine atom; R³ represents ahydrogen atom; X represents an oxygen atom; and Ar represents a phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl,3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl,3,5-di-t-butyl-4-hydroxyphenyl, 3-trifluoromethylphenyl,3-chloro-4-fluorophenyl or 2-naphthyl group.
 54. The composition ofclaim 45, wherein:R⁰ represents a hydrogen atom; R¹ represents a2,4-dioxothiazolidin-5-yl-methyl group; R² represents a hydrogen atom;R³ represents a hydrogen atom; X represents an oxygen atom; and Arrepresents a phenyl, 3-chlorophenyl, 3-bromophenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl or 2-naphthyl group.55. The composition of claim 45, wherein the active compound is selectedfrom the group consistingof:5-[4-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione;5-[4-{2-[2-(3-trifluoromethylphenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione;andsalts thereof.
 56. A method for the treatment or prophylaxis ofdiabetes, obesity, hyperlipemia, hyperglycemia, complications ofdiabetes, obesity-related hypertension and osteoporosis in a mammalwhich may be human, which method comprises administering to said mammalan effective amount of an active compound, wherein the active compoundis selected from the group consisting of compounds of formula (I) asclaimed in claim 1;and pharmaceutically acceptable salts thereof. 57.The method of claim 56, wherein:R⁰ represents a hydrogen atom, a methylgroup or a hydroxymethyl group; R¹ represents a substituted alkyl grouphaving from 1 to 12 carbon atoms and substituted by at least 1 and nomore than 8 2,4-dioxothiazolidin-5yl groups; R² and R³ are the same ordifferent and each represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, a hydroxy group, a methoxy group, anethoxy group, a carboxy group, an alkoxycarbonyl group having from 2 to7 carbon atoms, an alkyl group having from 1 to 5 carbon atoms, a nitrogroup, a trifluoromethyl group or a substituted alkyl group having from1 to 12 carbon atoms and substituted by at least 1 and no more than 82,4-dioxothiazolidin-5yl groups; X represents an oxygen or sulfur atom;Ar represents a group of formula (II) or (III), defined in claim 56; R⁴represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromineatom, a hydroxy group, a hydroxymethyl group, a methoxy group, an ethoxygroup, an alkyl group having from 1 to 5 carbon atoms, an acetoxy group,a nitro group, a cyano group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group; R⁵ represents a hydrogen atom,a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, amethoxy group, an alkyl group having from 1 to 5 carbon atoms or a nitrogroup; and R⁶ represents a hydrogen atom, a fluorine atom, a chlorineatom, a hydroxy group, a methoxy group or a methyl group.
 58. The methodof claim 56, wherein:R⁰ represents a hydrogen atom or a methyl group; R¹represents a substituted alkyl group which has from 1 to 12 carbon atomsand which is substituted by at least 1 and no more than 62,4-dioxothiazolidin-5yl groups; R² represents a hydrogen atom, afluorine atom, a chlorine atom, a bromine atom, a hydroxy group, amethoxy group, an ethoxy group, an alkyl group having from 1 to 4 carbonatoms or a nitro group; R³ represents a hydrogen atom, a fluorine atom,a chlorine atom, a hydroxy group, a methoxy group, a methyl group or at-butyl group; X represents an oxygen or sulfur atom; and Ar representsa group of formula (II) or (III), defined in claim 56; R⁴ represents ahydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, ahydroxy group, a hydroxymethyl group, a methoxy group, an ethoxy group,an alkyl group having from 1 to 4 carbon atoms, an acetoxy group, anitro group, a benzyloxy group, a phenoxy group, a phenyl group or atrifluoromethyl group; R⁵ represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, a hydroxy group, a methoxy group or analkyl group having from 1 to 4 carbon atoms; and R⁶ represents ahydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, amethoxy group or a methyl group.
 59. The method of claim 56, wherein:R⁰represents a hydrogen atom or a methyl group; R¹ represents asubstituted alkyl group which has from 1 to 6 carbon atoms and which issubstituted by at least 1 and no more than 6 2,4-dioxothiazolidin-5ylgroups; R² represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a hydroxy group, a methoxy group, an ethoxy group or analkyl group having from 1 to 4 carbon atoms; R³ represents a hydrogenatom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxygroup, a methyl group or a t-butyl group; X represents an oxygen orsulfur atom; Ar represents a group of formula (II) or (III), defined inclaim 56; R⁴ represents a hydrogen atom, a fluorine atom, a chlorineatom, a bromine atom, a hydroxy group, a hydroxymethyl group, a methoxygroup, an ethoxy group, an alkyl group having from 1 to 4 carbon atoms,an acetoxy group, a nitro group, a benzyloxy group, a phenoxy group, aphenyl group or a trifluoromethyl group; R⁵ represents a hydrogen atom,a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, amethoxy group or an alkyl group having from 1 to 4 carbon atoms; R⁶represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxygroup, a methoxy group or a methyl group.
 60. The method of claim 56,wherein:R⁰ represents a hydrogen atom or a methyl group; R¹ represents asubstituted alkyl group which has from 1 to 3 carbon atoms and which issubstituted by at least 1 and no more than 4 2,4-dioxothiazolidin-5ylgroups; R² represents a hydrogen atom, a fluorine atom, a chlorine atom,a hydroxy group, a methoxy group or an alkyl group having from 1 to 4carbon atoms; R³ represents a hydrogen atom, a chlorine atom, a hydroxygroup, a methoxy group or a methyl group; X represents an oxygen atom;Ar represents a group of formula (II) or (III), defined in claim 56; R⁴represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromineatom, a hydroxy group, a hydroxymethyl group, a methoxy group, an ethoxygroup, an alkyl group having from 1 to 4 carbon atoms, an acetoxy group,a nitro group, a benzyloxy group, a phenoxy group, a phenyl group or atrifluoromethyl group; R⁵ represents a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, a hydroxy group, a methoxy group or analkyl group having from 1 to 4 carbon atoms; and R⁶ represents ahydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, amethoxy group or a methyl group.
 61. The method of claim 56, wherein:R⁰represents a hydrogen atom or a methyl group; R¹ represents asubstituted alkyl group which has from 1 to 3 carbon atoms and which issubstituted by at least 1 and no more than 4 2,4-dioxothiazolidin-5ylgroups; R² represents a hydrogen atom, a chlorine atom, a hydroxy group,a methoxy group or a methyl group; R³ represents a hydrogen atom or amethyl group; X represents an oxygen atom; Ar represents a group offormula (II) or (III), defined in claim 56; R⁴ represents a hydrogenatom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group,a hydroxymethyl group, a methoxy group, an ethoxy group, an alkyl grouphaving from 1 to 4 carbon atoms, an acetoxy group, a nitro group, abenzyloxy group, a phenoxy group, a phenyl group or a trifluoromethylgroup; R⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, a hydroxy group, a methoxy group or an alkyl grouphaving from 1 to 4 carbon atoms; R⁶ represents a hydrogen atom, ahydroxy group, a methoxy group or a methyl group.
 62. The method ofclaim 56, wherein:R⁰ represents a hydrogen atom; R¹ represents asubstituted alkyl group which has from 1 to 3 carbon atoms and which issubstituted by at least 1 and no more than 4 2,4-dioxothiazolidin-5ylgroups; R² represents a hydrogen atom, a chlorine atom, a hydroxy group,a methoxy group or a methyl group; R³ represents a hydrogen atom; Xrepresents an oxygen atom; Ar represents a group of formula (II) or(III), defined in claim 56; R⁴ represents a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, a methoxy group, an alkyl grouphaving from 1 to 4 carbon atoms, a phenoxy group or a trifluoromethylgroup; R⁵ represents a hydrogen atom, a chlorine atom, a methoxy groupor an alkyl group having from 1 to 4 carbon atoms; and R⁶ represents ahydrogen atom, a hydroxy group or a methoxy group.
 63. The method ofclaim 56, wherein:R⁰ represents a hydrogen atom; R¹ represents an alkylgroup which has from 1 to 3 carbon atoms and which is substituted by 1or 2 2,4-dioxothiazolidin-5-yl group; R² represents a hydrogen atom, achlorine atom or a hydroxy group; R³ represents a hydrogen atom; Xrepresents an oxygen atom; and Ar represents a phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl,3-phenoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,5-dichlorophenyl,3,5-di-t-butyl-4-hydroxyphenyl, 3,4,5-trimethoxyphenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 1-naphthyl or2-naphthyl group.
 64. The method of claim 56, wherein:R⁰ represents ahydrogen atom; R¹ represents a methyl, 2-methoxycarbonylethyl,bis(methoxycarbonyl)-methyl, hydroxymethyl, 2-hydroxyethyl,1,2-dihydroxy 2,4-dioxothiazolidin-5-yl-methyl group; R² represents ahydrogen atom or a chlorine atom; R³ represents a hydrogen atom; Xrepresents an oxygen atom; and Ar represents a phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl,3-methylphenyl, 3-methoxyphenyl, 3,5-di-t-butyl-4-hydroxyphenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl or 2-naphthyl group.65. The method of claim 56, wherein:R⁰ represents a hydrogen atom; R¹represents a 2,4-dioxothiazolidin-5-yl-methyl group; R² represents ahydrogen atom; R³ represents a hydrogen atom; X represents an oxygenatom; and Ar represents a phenyl, 3-chlorophenyl, 3-bromophenyl,3-trifluoromethylphenyl, 3-chloro-4-fluorophenyl or 2-naphthyl group.66. The method of claim 56, wherein the active compound is selected fromthe group consistingof:5-[4-{2-[2-(3-chlorophenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione;5-[4-{2-[2-(3-trifluoromethylphenyl)-2-hydroxyethylamino]propoxy}benzyl]thiazolidine-2,4-dione;andsalts thereof.